Lysine demethylase inhibitors for diseases and disorders associated with flaviviridae

ABSTRACT

The invention relates to methods and compositions for the treatment or prevention of Flaviviridae infections. In particular, the invention relates to an LSD1 inhibitor for use in treating or preventing Flaviviridae infections, including hepatitis C virus infections.

FIELD OF THE INVENTION

The invention relates to methods and compositions for the treatment orprevention of diseases and disorders associated with Flaviviridae and inparticular hepatitis C virus infection and viral hepatitis. Theinvention also relates to an LSD1 inhibitor for use in treating orpreventing diseases and disorders associated with Flaviviridae and inparticular hepatitis C virus infection and viral hepatitis.

BACKGROUND OF THE INVENTION

One of the most dangerous and insidious classes of viruses that hasenormous economic impact in terms of health care costs and associatedburdens is the Flaviviridae which include the well know hepatitis Cvirus (HCV) which cause significant health problems world-wide, as wellas other viruses such as West Nile Virus (WNV) and Dengue or YellowFever virus which can be deadly with the potential for catastrophicepidemics.

The Flaviviridae are characterized as being positive sense singlestranded RNA viruses that have a genome of about 10 Kb that generallyencodes one long ORF composed of a number of genes that are transcribedas a large polyprotein. The large polyprotein is processed to yielddifferent enzymatic and structural proteins which go on to assist in RNAreplication and viral propagation with the assistance of host cellfactors. It is thought that the lifecycle of Flaviviridae does not gothrough replicative DNA intermediates.

Disease caused by hepatitis C virus is an enormous burden on the world'shealth systems. HCV is a major cause of liver disease throughout theworld. It is estimated that upwards of 10,000 deaths per year areattributable to HCV in the United States. About four million people inthe United States have antibodies to HCV. It is estimated that well over150 million people worldwide are chronically infected with HCV. Chronichepatitis C can cause hepatitis, cirrhosis, liver failure, and livercancer (hepatocellular carcinoma). There are a variety of subtypes ofHCV including at least 6 major genotypes and 50 subtypes. As with manyother viruses, HCV is known to mutate quickly, and changes in theenvelope protein may help the virus avoid the immune system of the host.

Efforts to combat HCV have been met with limited success. Vaccines andimmunoglobulin products for preventing HCV have been in development butare not currently available. Given the rapidly mutating nature of thevirus and the variety of variants of HCV, it is a daunting task and ifpossible, it will likely take a long time to develop such products forprevention of HCV infection. The only preventative strategies relate tothe ability to stop transmission of the virus by screening bloodsupplies and educating the public regarding high-risk groups andbehaviors.

Two treatments are available in the United States for those infectedwith HCV: monotherapy treatment with alpha interferon or combinationtherapy with alpha interferon and ribavirin. Combination therapy appearsto be the most efficacious treatment and therefore is the treatment ofchoice in the United States.

Alpha interferon monotherapy can be effective in treating chronic HCV,but it is not effective against all HCV infections and there can beunwanted side effects associated with this treatment option. The othertreatment option is a combination therapy with alpha interferon andribavirin. Again, there are undesirable side effects associated withthis combination therapy.

Despite years of intensive research aimed at developing treatments andprophylactic measures against HCV, there is a need for new improvedtreatments of HCV.

A new class of compounds for treating HCV targets the viral protease.Telaprevir, recently approved by the FDA, is the front runner in thiscategory, with first in class blockbuster potential. Other advancedclinical programs include nucleoside and non-nucleoside polymeraseinhibitors which target the viral RNA polymerase.

The mechanisms that viruses use to propagate themselves involvesco-opting certain aspect of their host cell to enter, be transported tothe correct location in the cell (e.g., nucleus) for replication orestablishment of latency, depart an infected cell and are only beginningto be understood on a general level. One long standing difficult goal inantiviral research has been the search of host cell factors that can betarget for treating and preventing viral infection.

A group of enzymes known as lysine methyl transferases and lysinedemethylases are involved in histone lysine modifications. Oneparticular human lysine demethylase enzyme called Lysine SpecificDemethylase-1 (LSD1) was recently discovered (Shi et al. (2004) Cell119:941) and shown to be involved in histone lysine methylation. LSD1has a fair degree of structural similarity, and amino acididentity/homology to polyamine oxidases and monoamine oxidases, all ofwhich (i.e., MAO-A, MAO-B and LSD1) are flavin dependent amine oxidaseswhich catalyze the oxidation of nitrogen-hydrogen bonds and/ornitrogen-carbon bonds. Although the main target of LSD1 appears to bemono- and di-methylated histone lysines, specifically H3K4 and H3K9,there is evidence in the literature that LSD1 can demethylate methylatedlysines on non-histone proteins like p53, E2F1, Dnmt1 and STAT3.

Several groups have reported LSD1 inhibitors in the literature. Sharmaet al. recently reported a new series of urea and thiourea analogs basedon an earlier series of polyamines which were shown to inhibit LSD1 andmodulate histone methylation and gene expression in cells (J. Med. Chem.2010 PMID: 20568780 [PubMed—as supplied by publisher]). Sharma et al.note that “To date, only a few existing compounds have been shown toinhibit LSD1.” Some efforts were made to make analogs of the histonepeptide that is methylated by the enzyme, other efforts have focused onmore small molecule like molecules based on known MAO inhibitors. Goodenet al. reported trans-2-arylcyclopropylamine analogues that inhibit LSD1with Ki values in the range of 188-566 micromolar (Gooden et al. ((2008)Bioorg. Med. Chem. Let. 18:3047-3051)). Most of these compounds weremore potent against MAO-A as compared to MAO-B. Ueda et al. ((2009) J.Am. Chem Soc. 131(48):17536-17537) reported cyclopropylamine analogsselective for LSD1 over MAO-A and MAO-B that were designed based onreported X-ray crystal structures of these enzymes with aphenylcyclopropylamine-FAD adduct and a FAD-N-propargyl lysine peptide.The reported IC50 values for phenylcyclopropylamine were about 32micromolar for LSD1 whereas as compounds 1 and 2 had values of 2.5 and1.9 micromolar respectively.

Importantly, studies have also been conducted on amine oxidase inhibitorcompounds to determine selectivity for MAO-A versus MAO-B since MAO-Ainhibitors can cause dangerous side-effects (see e.g., Yoshida et al.(2004) Bioorg. Med. Chem. 12(10):2645-2652; Hruschka et al. (2008) BiorgMed Chem. (16):7148-7166; Folks et al. (1983) J. Clin. Psychopharmacol.(3)249; and Youdim et al. (1983) Mod. Probl. Pharmacopsychiatry(19):63).

Currently the treatments available for HCV and related diseases haveserious drawbacks. There is a need for new drugs for these diseases thattarget novel points of intervention in the disease processes and avoidside-effects associated with certain targets. The invention describedherein below provides an entirely new class of HCV antivirals.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to the treatment or prevention ofFlaviviridae infection and diseases caused by such viruses, and inparticular hepatitis C. The inventors have unexpectedly found thatinhibitors of LSD1 reduce HCV RNA replication. This finding isunexpected since HCV is not thought to go through a DNA replicativeintermediate and the most well characterized functions of LSD1 relate tohistone methylation and its effect on modulating DNA transcription.Advantageously, the use of selective LSD1 inhibitors or dual LSD1/MAOBinhibitors avoids side-effects associated with targets such as MAOA.Furthermore, the invention is also based on the unexpected finding thatLSD1 inhibitors targeting a host cell protein inhibit HCV RNAreplication and therefore avoid problems with targeting a viral activitylike viral proteases or polymerases, which result in the generation ofresistant strains. The inventors found that administration of LSD1inhibitors chronically was well tolerated in a mammal (selective anddual LSD1/MAOB inhibitors). Thus, the inventors have unexpectedly foundthat LSD1 inhibition, particularly selective LSD1 inhibition orLSD1/MAOB dual inhibitions, is a new therapeutic approach to treatingand preventing Flaviviridae infection and related diseases anddisorders.

The present invention provides for the treatment and prevention ofFlaviviridae infection and diseases caused by Flaviviridae infection. Inparticular, the invention provides compositions and methods that affectthe ability of Flaviviridae to utilize the host's cellular machinery aspart of the virus' lifecycle. The invention relates to the finding thatinterfering with the normal ability of viruses to utilize the host cellmachinery with LSD1 inhibitors reduces HCV RNA replication.

The Flaviviridae infections and the diseases caused by Flaviviridae tobe treated or prevented in accordance with the present inventioninclude, without being limited thereto, infections and diseases causedby Hepatitis C Virus, Yellow fever virus, West Nile Virus, Dengue Virusor Japanese encephalitis virus. The diseases caused by Flaviviridaecomprise, e.g., Hepatitis C infection, Yellow fever, Dengue fever,Japanese encephalitis, or West Nile encephalitis. The inventionparticularly relates to the treatment or prevention of an infection ordisease caused by Hepatitis C Virus.

Thus, the treatment and prevention of Flaviviridae infection anddiseases caused by Flaviviridae according to the invention comprisesadministering to an individual in need of treatment, a therapeuticallyeffective amount of a LSD1 inhibitor. The individual in need oftreatment can be a human or e.g., another mammal. In one embodiment, theFlaviviridae is Hepatitis C Virus, Yellow fever virus, West Nile Virus,Dengue Virus or Japanese encephalitis virus. In particular, theFlaviviridae may be Hepatitis C Virus, West Nile Virus or Dengue Virus.In one embodiment, the Flaviviridae is Hepatitis C Virus. In oneembodiment, the disease caused by Flaviviridae is Hepatitis C infection,Yellow fever, Dengue fever, Japanese encephalitis, or West Nileencephalitis. In another embodiment, the disease caused by Flaviviridaeis Hepatitis C infection.

Accordingly, the invention provides HCV treatment and prevention methodsand compositions based on inhibitors of LSD1.

In one embodiment, the invention provides a method of affecting theability of HCV to replicate RNA. According to this method, an effectiveamount of a pharmaceutical composition comprising a LSD1 inhibitor isadministered to an individual in need of treatment. The composition ispreferably a small molecule inhibitor of LSD1.

In another embodiment, the invention provides a method of treating anindividual infected with HCV by administering to the individual atherapeutically effective amount of a LSD1 inhibitor. According to oneaspect of this embodiment, the LSD1 inhibitor is an irreversible or areversible amine oxidase inhibitor. In one aspect, the irreversibleamine oxidase inhibitor is a phenylcyclopropylamine derivative oranalog, a phenelzine derivative or analog, or a propargylaminederivative or analog.

In yet another embodiment, the present invention provides a method oftreating an individual infected with HCV by administering, to a patientin need of therapeutic or prophylactic treatment, an amount of a LSD1inhibitor effective to reduce HCV RNA replication. Such treatments canbe used to suppress the symptoms of HCV i.e., suppressive therapy, orfor treating episodic outbreaks i.e., episodic therapy.

The invention further provides a method of identifying compounds thathave HCV antiviral activity. More particularly, the method involvesidentifying compounds that inhibit LSD1 and then testing the LSD1inhibitors in an HCV antiviral assay. According to this embodiment anassay system is employed to detect compounds and/or compositions thataffect the ability of the virus to propagate itself.

In one aspect, the invention is a method of treating or preventing asymptom of HCV infection in an individual infected with HCV comprisingidentifying a patient in need of such treatment and administering tosaid individual for a sufficient period of time an amount of a LSD1inhibitor sufficient to improve the symptom or reduce the rate ofdecline of the symptom thereby treating or preventing said symptom ofHCV infection. In a related aspect, the invention is the use of a LSD1inhibitor in an amount sufficient to modulate LSD1 activity for treatingor preventing liver disease in an individual infected with HCV. In aspecific aspect, the liver disease is hepatitis or hepatocellularcarcinoma. In one embodiment of this aspect, the amount of LSD1inhibitor administered is sufficient to modulate or inhibit LSD1activity while not substantially inhibiting MAOA activity, therebyavoiding or reducing side-effects associated with administration of MAOAinhibitors.

In one aspect, the invention relates to a pharmaceutical composition foruse in treating Flaviviridae comprising an anti-Flaviviridae effectiveamount of a LSD1 inhibitor. In one embodiment, the Flaviviridae isHepatitis C Virus, Yellow fever virus, West Nile Virus, Dengue Virus orJapanese encephalitis virus. In particular, the Flaviviridae may beHepatitis C Virus, West Nile Virus or Dengue Virus. In one embodiment,the Flaviviridae is Hepatitis C Virus.

In one aspect, the invention relates to a pharmaceutical composition foruse in treating HCV infection comprising an anti-HCV effective amount ofa LSD1 inhibitor.

In one aspect, the invention relates to a method of combinationtreatment. According to this method a LSD1 inhibitor and a secondanti-HCV agent are administered to an individual (e.g. a human) in needof treatment. In one aspect, the second anti-HCV agent is preferablychosen from an interferon agent, a nucleoside polymerase inhibitor, anon-nucleoside polymerase inhibitor, a protease inhibitor or a NS5Ainhibitor. In one aspect, the protease inhibitor is Telaprevir,Boceprevir, TMC435350, R7227, or BI201335. In one aspect, the nucleosidepolymerase inhibitor is R7128, PSI-7851, or IDX184.

In one aspect, the invention relates to a composition for combinationtreatment of HCV. Accordingly, the pharmaceutical composition of thisaspect comprises a LSD1 inhibitor and a second anti-HCV agent along witha pharmaceutically acceptable carrier or excipient. In one aspect, thesecond agent is chosen from a nucleoside polymerase inhibitor, anon-nucleoside polymerase inhibitor, a protease inhibitor or a NS5Ainhibitor. In one aspect, the protease inhibitor is Telaprevir,Boceprevir, TMC435350, R7227, or BI201335. In one aspect, the nucleosidepolymerase inhibitor is R7128, PSI-7851, or IDX184. In one aspect, thenon-nucleoside polymerase inhibitor is PF-868554 or GS-9190. In oneaspect, the NS5A inhibitor is BMS-790052.

In one aspect, the invention is a method or pharmaceutical compositionfor treating an individual co-infected with HCV and HBV. Accordingly,the method comprises identifying an individual in need of treatment andadministering to said individual a therapeutically effective amount ofan LSD1 inhibitor. In a more specific aspect, the method furthercomprises administering to said individual one or more anti-HCV oranti-HBV agents.

In one aspect, the sufficient period of time for administering the LSD1inhibitors is for 5 or more days to the individual, more preferably from5 days to 4 years, even more preferably from 5 days to two years, yeteven more preferably for 15 days to 2 years, and again yet even morepreferably from 15 days to 1 year. In one aspect, the LSD1 inhibitor isadministered daily in amount sufficient to yield a Cmaxabove the IC50value for the LSD1 inhibitor. A person skilled in the art willappreciate that the Cmax should be above the IC50 value in the samespecies (e.g., in a human) in which the Cmax is to be measured.

The invention also relates to an LSD1 inhibitor for use in any of theabove-described methods.

Accordingly, the invention relates to an LSD1 inhibitor (or apharmaceutical composition comprising an LSD1 inhibitor and apharmaceutically acceptable carrier) for use in the treatment orprevention of a Flaviviridae infection or a disease caused byFlaviviridae. In one embodiment, the Flaviviridae is Hepatitis C Virus,Yellow fever virus, West Nile Virus, Dengue Virus or Japaneseencephalitis virus. In particular, the Flaviviridae may be Hepatitis CVirus, West Nile Virus or Dengue Virus. In one embodiment, theFlaviviridae is Hepatitis C Virus. In a preferred embodiment, theinvention relates to an LSD1 inhibitor (or a pharmaceutical compositioncomprising an LSD1 inhibitor and a pharmaceutically acceptable carrier)for use in the treatment or prevention of HCV infection or a diseasecaused by HCV. In another embodiment, the invention relates to an LSD1inhibitor (or a pharmaceutical composition comprising an LSD1 inhibitorand a pharmaceutically acceptable carrier) for use in the treatment orprevention of a symptom of HCV infection in an individual infected withHCV. In another embodiment the invention relates to an LSD1 inhibitor(or a pharmaceutical composition comprising an LSD1 inhibitor and apharmaceutically acceptable carrier) for use in the treatment orprevention of a liver disease in an individual infected with HCV. In apreferred embodiment, the liver disease is hepatitis or hepatocellularcarcinoma.

The present invention furthermore provides a LSD1 inhibitor to beadministered in combination with one or more further therapeutic agentsfor use in the treatment or prevention of a Flaviviridae infection or adisease caused by Flaviviridae. The one or more further therapeuticagents may, for example, be antiviral agents (such as, e.g., anti-HCVagents). In particular the invention provides a LSD1 inhibitor to beadministered in combination with a second anti-HCV agent, for use in thetreatment or prevention of HCV infection or a disease caused by HCV. Theadministration of the LSD1 inhibitor and the one or more furthertherapeutic agents, such as a second anti-HCV agent, may, e.g., besimultaneous/concomitant or sequential/separate. In one embodiment, thesecond anti-HCV agent is preferably chosen from an interferon agent, anucleoside polymerase inhibitor, a non-nucleoside polymerase inhibitor,a protease inhibitor or a NS5A inhibitor. In one embodiment, theprotease inhibitor is Telaprevir, Boceprevir, TMC435350, R7227, orBI201335. In another embodiment, the nucleoside polymerase inhibitor isR7128, PSI-7851, or IDX184. In another embodiment, the non-nucleosidepolymerase inhibitor is PF-868554 or GS-9190. In another embodiment, theNS5A inhibitor is BMS-790052.

In one embodiment, the LSD1 inhibitor to be used in accordance with thepresent invention, in particular in the treatment or prevention ofFlaviviridae infection or a disease caused by Flaviviridae, includingHCV infection or a disease caused by HCV, is a small molecule inhibitorof LSD1. In a preferred embodiment, the LSD1 inhibitor is a selectiveLSD1 inhibitor or a dual LSD1/MAO-B inhibitor. In another embodiment,the LSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound, aphenclzine compound or a propargylamine compound, and is more preferablya 2-cyclylcyclopropan-1-amine compound. Said 2-cyclylcyclopropan-1-aminecompound is preferably a 2-arylcyclopropan-1-amine compound or a2-heteroarylcyclopropan-1-amine compound, more preferably a2-phenylcyclopropan-1-amine compound, a 2-pyridinylcyclopropan-1-aminecompound or a 2-thiazolylcyclopropan-1-amine compound.

Thus, the invention also relates to the following embodiments:

-   1. A method of treating or preventing Flaviviridae infection or an    associated disease or disorder comprising identifying an individual    in need of such treatment and administering to said individual a    LSD1 inhibitor.-   2. The method as in 1 wherein said Flaviviridae infection is    Hepatitis C Virus, West Nile Virus or Dengue Virus.-   3. The method as in 1 wherein said Flaviviridae infection is    Hepatitis C virus.-   4. The method as in 1 wherein said LSD1 inhibitor is a reversible or    irreversible amine oxidase inhibitor.-   5. The method as in 1 wherein said LSD1 inhibitor inhibits    Flaviviridae RNA replication.-   6. The method as in 1 wherein said LSD1 inhibitor is a    phenylcyclopropylamine derivative or analog, a phenelzine derivative    or analog, or a propargylamine derivative or analog.-   7. The method as in 1 wherein said LSD1 has a therapeutic index of    10 or great.-   8. The method as in 1 wherein said LSD1 has a therapeutic index of    100 or great.-   9. The method as in 1 further comprising administering to said    individual a second anti-HCV agent.-   10. The method as in 9 wherein said second anti-HCV agent is an    interferon agent, a protease inhibitor, a nucleoside polymerase    inhibitor, a non-nucleoside polymerase inhibitor, or a NS5A    inhibitor.-   11. A LSD1 inhibitor or a pharmaceutical composition comprising a    LSD1 inhibitor for use in treating or preventing Flaviviridae    infection or a related disease or disorder.-   12. The LSD1 inhibitor as in 11 wherein said Flaviviridae infection    is HCV infection.-   13. A LSD1 inhibitor or a pharmaceutical composition comprising a    LSD1 inhibitor and a second anti-HCV agent for use in treating or    preventing Flaviviridae infection or a related disease or disorder.-   14. The LSD1 inhibitor as in 13 wherein said Flaviviridae infection    is HCV infection.-   15. The LSD1 inhibitor as in 13 or 14 wherein said second anti-HCV    is an interferon agent, a protease inhibitor, a nucleoside    polymerase inhibitor, a non-nucleoside polymerase inhibitor, or a    NS5A inhibitor.-   16. The LSD1 inhibitor as in 11 to 15 wherein said LSD1 inhibitor is    a reversible or irreversible amine oxidase inhibitor.-   17. The LSD1 inhibitor as in 11 to 15 wherein said LSD1 inhibitor is    an irreversible amine oxidase inhibitor.-   18. The LSD1 inhibitor as in 11 to 15 wherein said LSD1 inhibitor is    a phenylcyclopropylamine derivative or analog, a phenelzine    derivative or analog, or a propargylamine derivative or analog.-   19. The method as in 6 or the LSD1 inhibitor as in 18 wherein said    phenelzine analog or derivative: (a) has one, two, three, four or    five substituents on the phenyl group; (b) has the phenyl group    substituted with (exchanged for) an aryl or heterocyclyl group    wherein said aryl or heterocyclyl group has zero, one, two, three,    four or five substituents; or (c) as in (a) or (b) and having a    substitution on the terminal nitrogen of the hydrazine group.-   20. The method as in 6 or the LSD1 inhibitor as in 18 wherein said    propargylamine derivative or analog is a pargyline derivative or    analog wherein: (a) said pargyline derivative or analog has one,    two, three, four or five substituents on the phenyl group; (b) said    pargyline derivative or analog has the phenyl group substituted with    (exchanged for) an aryl or heterocyclyl group wherein said aryl or    heterocyclyl group has zero, one, two, three, four or five    substituents; or (c) as in (a) or (b) wherein the propargylmine    moiety of pargyline has one or two substituents.-   21. The method as in 6 or the LSD1 inhibitor as in 18 wherein said    phenylcyclopropylamine derivative or analog: (a) has one, two,    three, four or five substituents on the phenyl group; or (b) the    phenyl group substituted with (exchanged for) an aryl or    heterocyclyl group wherein said aryl or heterocyclyl group has zero,    one, two, three, four or five substituents; or (c) as in (a) or (b)    and additionally having one or two substituents on the amino group    of the cyclopropylamine core.-   22. A method of treating or preventing HCV and HBV co-infection    comprising identifying an individual in need of such treatment and    administering to said individual a LSD1 inhibitor and optionally a    second anti-HCV agent or anti-HBV agent.-   23. The LSD1 inhibitor as in 1-21 wherein said LSD1 inhibitor has a    therapeutic index of 100 or greater.-   24. The method of 6 or 21 or the LSD1 inhibitor of 18 or 21 wherein    the phenylcyclopropylamine derivative or analog has the 1S,2R    configuration in respect to the substituents on the cyclopropyl    ring.-   25. The method of 6 or 21 or the LSD1 inhibitor of 18 or 21 wherein    the phenylcyclopropylamine derivative or analog has the 1R,2S    configuration in respect to the substituents on the cyclopropyl    ring.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Optimization of Selective LSD1 Inhibitors. FIG. 1 summarizesstructure-activity relationship evolution of increased potency towardsLSD1 as compared to MAOA and/or MAOB from compounds that were notselective (e.g., tranylcypromine) to compounds that are selectiveinhibitors of LSD1 with IC50 values in the low nanomolar range.

FIG. 2 Optimization of Dual LSD1/MAOB Inhibitors. FIG. 2 summarizesstructure-activity relationship evolution of increased potency towardsLSD1 and MAOB as compared to MAOA from compounds that were not selectivefor LSD1 and MAOB (e.g., tranylcypromine). The dual LSD1/MAOB compoundshave IC50 values for these two targets in the low nanomolar range.

FIG. 3 Compound Dual-1 Increases Histone Methylation. FIG. 3A. shows theresults of a western blot stained for H3K4 methylation with SH-SY5Ycells grown in the presence of Compound Dual-1 (at 100 μM) or parnate(“PNT”) (at 250 μM) for 1, 2, and 3 days, showing that this compound,Dual-1, increases H3K4 methylation in cells in a time dependent manner.FIG. 3B is a graph showing quantification of the results shown in FIG.3A.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have unexpectedly found that inhibitors of LSD1 can reduceHCV RNA replication. This finding is unexpected since HCV is thought notto go through a DNA replicative intermediate and the most wellcharacterized functions of LSD1 relate to histone methylation and itseffect on modulating DNA transcription. Thus, the inventors have shownthat LSD1 inhibitors inhibit the ability of RNA viruses such as HCV, amember of the Flaviviridae family of viruses, to replicate their RNA.This finding is significant since RNA viruses are known to mutaterapidly and develop resistance to therapeutics targeted to viralproteins. Thus, the methods and compositions of the invention can beuseful for treating viruses and viral infections resistant to currenttreatments or treatment that are in developments and eventuallyclinically approved. Additionally, the methods and compositions of theinvention can be useful for treating viruses or viral infection whilereducing the likelihood of the virus or viral infection to developingresistance to current treatments or treatment that are in developmentsand eventually clinically approved. Other advantages and more details ofthe invention are described in more detail below.

A medicinal chemistry effort undertaken by some of the inventorsresulted in the synthesis and identification of small molecule, potentselective LSD1 inhibitors and potent dual inhibitors of LSD1 and MAOB.This effort resulted in the identification of a number of compoundshaving different selectivities for LSD1, MAOA, and MAOB. See FIG. 1.

Subsequent studies of some of the optimized compounds in a neuralderived cell line and other cell lines indicted that both selective LSD1inhibitors and dual inhibitors of LSD1 and MAOB can increase histonemethylation levels at the cellular level, indicating that thesecompounds inhibit cellular lysine demethylase activity. Furthermore,these LSD1 inhibitors show dose dependent effects on gene expressionlevels in these cells.

The LSD1 inhibitors were able to be administered safely to mammalschronically at doses that are thought to achieve levels of the inhibitorsufficient for causing a biological effect.

Lastly, Compound X, a potent selective LSD1 inhibitor was shown to haveactivity in the 300-500 nanomolar range in an HCV RNA replication assaywith a “therapeutic index” of greater than 100. See Example 5. Withoutbeing bound by theory, it is believed that LSD1 inhibitors, includingselective LSD1 inhibitors and dual LSD1/MAO-B inhibitors, inhibit HCVRNA replication and have use for treating or preventing Flaviviridaeinfection or an associated disease or disorder. More specifically, it isbelieved that LSD1 inhibitors, as a result of this invention, have usein treating or preventing HCV or an associated disease or disorder.

Methods of Treatment or Prevention and Disease

The invention relates to methods of treatment or prevention of diseasesor disorders related to Flaviviridae infection.

In one embodiment, the invention is the use of a LSD1 inhibitor fortreating or preventing Flaviviridae infection. In a related aspect, theinvention is a method of treating or preventing Flaviviridae infectioncomprising administering a LSD1 inhibitor to an individual. In anotherrelated aspect, the invention is a method of treating or preventingFlaviviridae infection comprising administering a LSD1 inhibitor to anindividual in need of such treatment. In yet another related aspect, theinvention is a method of treating or preventing Flaviviridae infectioncomprising identifying an individual in need of such treatment orprevention and administering a LSD1 inhibitor to said individual. In oneembodiment, the Flaviviridae is Hepatitis C Virus, Yellow fever virus,West Nile Virus, Dengue Virus or Japanese encephalitis virus. In aspecific embodiment, the Flaviviridae is HCV, Dengue virus or West Nilevirus. In another specific embodiment, the Flaviviridae is HCV. Inanother specific embodiment, the Flaviviridae is WNV. In anotherspecific embodiment, the Flaviviridae is Dengue virus. In anotherspecific embodiment, the Flaviviridae is yellow fever virus. In oneaspect, the LSD1 inhibitor is a small molecule inhibitor of LSD1. In oneaspect, the LSD1 inhibitor is a selective inhibitor of LSD1. In oneaspect, the LSD1 inhibitor is a selective inhibitor of LSD1 and MAOB(i.e. a dual LSD1/MAO-B inhibitor). In one aspect, the LSD1 inhibitor isan irreversible or a reversible amine oxidase inhibitor. In one aspect,the irreversible amine oxidase inhibitor is a phenylcyclopropylaminederivative or analog, a phenelzine derivative or analog, or apropargylamine derivative or analog. In one aspect, the LSD1 inhibitoris a 2-cyclylcyclopropan-1-amine compound, a phenelzine compound, or apropargylamine compound, more preferably a 2-cyclylcyclopropan-1-aminecompound, still more preferably a 2-arylcyclopropan-1-amine compound ora 2-heteroarylcyclopropan-1-amine compound, and even more preferably a2-phenylcyclopropan-1-amine compound, 2-pyridinylcyclopropan-1-aminecompound or a 2-thiazolylcyclopropan-1-amine compound. In one aspect ofthis embodiment, the LSD1 inhibitor has a therapeutic index of 10 orgreater. In one aspect of this embodiment, the LSD1 inhibitor has atherapeutic index of 50 or greater. In one aspect of this embodiment,the LSD1 inhibitor has a therapeutic index of 100 or greater.

In one embodiment, the invention is the use of a LSD1 inhibitor forinhibiting Flaviviridae RNA replication. In a related aspect, theinvention is a method of inhibiting Flaviviridae RNA replicationcomprising administering a LSD1 inhibitor to an individual. In anotherrelated aspect, the invention is a method of inhibiting Flaviviridae RNAreplication comprising administering a LSD1 inhibitor to an individualin need of such treatment. In yet another related aspect, the inventionis a method of inhibiting Flaviviridae RNA replication comprisingidentifying an individual in need of such treatment or prevention andadministering a LSD1 inhibitor to said individual. In one aspect, theLSD1 inhibitor is a small molecule inhibitor of LSD1. In one aspect, theLSD1 inhibitor is a selective inhibitor of LSD1. In one aspect, the LSD1inhibitor is a selective inhibitor of LSD1 and MAOB. In one aspect, theLSD1 inhibitor is an irreversible or a reversible amine oxidaseinhibitor. In one aspect, the irreversible amine oxidase inhibitor is aphenylcyclopropylamine derivative or analog, a phenelzine derivative oranalog, or a propargylamine derivative or analog. In one aspect, theLSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound, a phenelzinecompound, or a propargylamine compound, more preferably a2-cyclylcyclopropan-1-amine compound, still more preferably a2-arylcyclopropan-1-amine compound or a 2-heteroarylcyclopropan-1-aminecompound, and even more preferably a 2-phenylcyclopropan-1-aminecompound, 2-pyridinylcyclopropan-1-amine compound or a2-thiazolylcyclopropan-1-amine compound. In one aspect of thisembodiment, the LSD1 inhibitor has a therapeutic index of 10 or greater.In one aspect of this embodiment, the LSD1 inhibitor has a therapeuticindex of 50 or greater. In one aspect of this embodiment, the LSD1inhibitor has a therapeutic index of 100 or greater. In one embodiment,the Flaviviridae is Hepatitis C Virus, Yellow fever virus, West NileVirus, Dengue Virus or Japanese encephalitis virus. In one aspect ofthis embodiment, the Flaviviridae is HCV, WNV, or Dengue Virus. In oneaspect of this embodiment, the Flaviviridae is HCV. In one aspect ofthis embodiment, the Flaviviridae is WNV. In one aspect of thisembodiment, the Flaviviridae is Dengue Virus. In one aspect of thisembodiment, the Flaviviridae is Yellow fever Virus.

In one embodiment, the invention is the use of a LSD1 inhibitor fortreating or preventing HCV infection. In a related aspect, the inventionis a method of treating or preventing HCV infection comprisingadministering a LSD1 inhibitor to an individual. In another relatedaspect, the invention is a method of treating or preventing HCVinfection comprising administering a LSD1 inhibitor to an individual inneed of such treatment. In yet another related aspect, the invention isa method of treating or preventing HCV infection comprising identifyingan individual in need of such treatment or prevention and administeringa LSD1 inhibitor to said individual. In one aspect, the LSD1 inhibitoris a small molecule inhibitor of LSD1. In one aspect, the LSD1 inhibitoris a selective inhibitor of LSD1. In one aspect, the LSD1 inhibitor is aselective inhibitor of LSD1 and MAOB. In one aspect, the LSD1 inhibitoris an irreversible or a reversible amine oxidase inhibitor. In oneaspect, the irreversible amine oxidase inhibitor is aphenylcyclopropylamine derivative or analog, a phenelzine derivative oranalog, or a propargylamine derivative or analog. In one aspect, theLSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound, a phenelzinecompound, or a propargylamine compound, more preferably a2-cyclylcyclopropan-1-amine compound, still more preferably a2-arylcyclopropan-1-amine compound or a 2-heteroarylcyclopropan-1-aminecompound, and even more preferably a 2-phenylcyclopropan-1-aminecompound, 2-pyridinylcyclopropan-1-amine compound or a2-thiazolylcyclopropan-1-amine compound. In one aspect of thisembodiment, the LSD1 inhibitor has a therapeutic index of 10 or greater.In one aspect of this embodiment, the LSD1 inhibitor has a therapeuticindex of 50 or greater. In one aspect of this embodiment, the LSD1inhibitor has a therapeutic index of 100 or greater.

In one embodiment, the invention is the use of a LSD1 inhibitor forinhibiting HCV RNA replication. In a related aspect, the invention is amethod of inhibiting HCV RNA replication comprising administering a LSD1inhibitor to an individual. In another related aspect, the invention isa method of inhibiting HCV RNA replication comprising administering aLSD1 inhibitor to an individual in need of such treatment. In yetanother related aspect, the invention is a method of inhibiting HCV RNAreplication comprising identifying an individual in need of suchtreatment or prevention and administering a LSD1 inhibitor to saidindividual. In one aspect, the LSD1 inhibitor is a small moleculeinhibitor of LSD1. In one aspect, the LSD1 inhibitor is a selectiveinhibitor of LSD1. In one aspect, the LSD1 inhibitor is a selectiveinhibitor of LSD1 and MAOB. In one aspect, the LSD1 inhibitor is anirreversible or a reversible amine oxidase inhibitor. In one aspect, theirreversible amine oxidase inhibitor is a phenylcyclopropylaminederivative or analog, a phenelzine derivative or analog, or apropargylamine derivative or analog. In one aspect, the LSD1 inhibitoris a 2-cyclylcyclopropan-1-amine compound, a phenelzine compound, or apropargylamine compound, more preferably a 2-cyclylcyclopropan-1-aminecompound, still more preferably a 2-arylcyclopropan-1-amine compound ora 2-heteroarylcyclopropan-1-amine compound, and even more preferably a2-phenylcyclopropan-1-amine compound, 2-pyridinylcyclopropan-1-aminecompound or a 2-thiazolylcyclopropan-1-amine compound. In one aspect ofthis embodiment, the LSD1 inhibitor has a therapeutic index of 10 orgreater. In one aspect of this embodiment, the LSD1 inhibitor has atherapeutic index of 50 or greater. In one aspect of this embodiment,the LSD1 inhibitor has a therapeutic index of 100 or greater.

The patient, subject, or individual, such as the individual in need oftreatment or prevention, may be e.g., a eukaryote, an animal, avertebrate animal, a mammal, a rodent (e.g., a guinea pig, a hamster, arat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), afeline (e.g., a cat), an equine (e.g., a horse), a primate, a simian(e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape(e.g., gorilla, chimpanzee, orangutang, gibbon), or a human. The meaningof the terms “eukaryote”, “animal”, “mammal”, etc., is well known in theart and can, for example, be deduced from Wehner und Gehring (1995;Thieme Verlag). In the context of this invention, it is particularlyenvisaged that animals are to be treated which are economically,agronomically or scientifically important. Scientifically importantorganisms include, but are not limited to, mice, rats, rabbits, fruitflies like Drosophila melagonaster and nematodes like Caenorhabditiselegans. Non-limiting examples of agronomically important animals aresheep, cattle and pig, while, for example, cats and dogs may beconsidered as economically important animals. Preferably, thesubject/patient/individual is a mammal; more preferably, thesubject/patient/individual is a human.

As used herein, in the context of diseases and disorders, the term“treating” refers to a slowing of or a reversal of the progress of thedisease. Treating a disease or disorder includes treating a symptomand/or reducing the symptoms of the disease.

As used herein, in the context of diseases and disorders, the term“preventing” refers to a slowing of the disease or of the onset of thedisease or the symptoms thereof. Preventing a disease or disorder caninclude stopping the onset of the disease or symptoms thereof.

As used herein, “second anti-HCV” refers to an anti-HCV different fromthe LSD1 inhibitor of the invention and which preferably does not actvia LSD1 inhibition.

As used herein, “therapeutic index” refers to the ratio between theconcentration of a drug that causes a lethal or toxic effect and theconcentration that causes a therapeutic effect, and can be expressed asTherapeutic Index=LD50/ED50 (in animals) or TD50/ED50 (in humans).“Selectivity index”, as used herein, is equivalent to “therapeuticindex”.

As used herein, “LSD1 inhibitor” refers to a molecule that directly orindirectly lowers or downregulates a biological activity of LysineDependent Demethylase 1 (LSD1). A LSD1 inhibitor may be any member of aclass of compounds (e.g. a small molecule or an antibody) that bindsLSD1 and inhibits a biological activity (e.g. demethylase activity) of aLSD1 protein or a protein complex in which LSD1 exerts its function(e.g. LSD1 being complexed to co-REST and/or other protein members ofthe nucleosome). A LSD1 inhibitor may also be any member of a class ofcompounds that decreases the expression of a nucleic acid encoding aLSD1 protein (e.g. an inhibitory nucleic acid, RNAi, such as a smallhairpin RNA).

As used herein “a small molecule inhibitor of LSD1” refers to an LSD1inhibitor having a molecular weight of less than 1000 daltons,preferably less than 700 daltons.

As used herein, the term “selective LSD1 inhibitor”, “LSD1 selectiveinhibitor” or “selective inhibitor of LSD1” refers to an LSD1 inhibitorwhich preferably has an IC50 value for LSD1 that is at least two-foldlower than its IC50 values for MAO-A and MAO-B. More preferably, aselective LSD1 inhibitor has an IC50 value for LSD1 which is at leastfive-fold lower than its IC50 values for MAO-A and MAO-B. Even morepreferably, a selective LSD1 inhibitor has an IC50 value for LSD1 whichis at least ten-fold lower than its IC50 values for MAO-A and MAO-B.Even more preferably, a selective LSD1 inhibitor has an IC50 value forLSD1 which is at least 20-fold lower than its IC50 values for MAO-A andMAO-B. Even more preferably, a selective LSD1 inhibitor has an IC50value for LSD1 which is at least 50-fold lower than its IC50 values forMAO-A and MAO-B. Even more preferably, a selective LSD1 inhibitor has anIC50 value for LSD1 which is at least 100-fold lower than its IC50values for MAO-A and MAO-B. The ability of a compound to inhibit LSD1and its IC50 values for LSD1, MAO-A and MAO-B are preferably to bedetermined in accordance with the experimental protocol described inExample 1.

As used herein, the term “selective inhibitor of LSD1 and MAOB”, “dualLSD1/MAO-B inhibitor”, “LSD1/MAO-B inhibitor”, “dual LSD1/MAOB selectiveinhibitor”, “dual inhibitor selective for LSD1 and MAO-B” or “dualinhibitor of LSD1 and MAO-B” refers to an LSD1 inhibitor whichpreferably has IC50 values for LSD1 and MAO-B which are at leasttwo-fold lower than its IC50 value for MAO-A. More preferably, a dualLSD1/MAO-B selective inhibitor has IC50 values for LSD1 and MAO-B whichare at least five-fold lower than its IC50 value for MAO-A. Even morepreferably, a dual LSD1/MAO-B selective inhibitor has IC50 values forLSD1 and MAO-B which are at least ten-fold lower than its IC50 value forMAO-A. Even more preferably, a dual LSD1/MAO-B selective inhibitor hasIC50 values for LSD1 and MAO-B which are at least 20-fold lower than itsIC50 value for MAO-A. The ability of a compound to inhibit LSD1 andMAO-B and its IC50 values for LSD1, MAO-A and MAO-B are preferably to bedetermined in accordance with the experimental protocol described inExample 1.

In another aspect, the invention is a method of treating HCV comprisingidentifying an individual in need of such treatment and administering tosaid individual for a sufficient period of time an amount of a LSD1inhibitor, preferably a selective LSD1 inhibitor, sufficient to treatHCV. In a related aspect, the invention is the use of a LSD1 inhibitor,preferably a selective LSD1 inhibitor, or a pharmaceutical compositioncomprising said LSD1 inhibitor (or said selective LSD1 inhibitor) in anamount sufficient to inhibit LSD1 activity for treating HCV. In aspecific aspect, said treatment reduces HCV RNA replication. In oneembodiment of this aspect, the amount of LSD1 inhibitor, preferably aselective LSD1 inhibitor, administered or that is in the pharmaceuticalcomposition is sufficient to modulate or inhibit LSD1 activity while notsubstantially inhibiting MAOA activity, thereby avoiding or reducingside-effects associated with administration of MAOA inhibitors. In aspecific aspect of this embodiment, preferably the amount of LSD1inhibitor administered per day to a human is from about 0.5 mg to about500 mg per day. More preferably the amount of LSD1 inhibitoradministered per day to a human is from about 0.5 mg to about 200 mg perday or is a pharmaceutical composition formulated in such a way as todeliver this amount of free base equivalent (or free acid equivalentdepending on the parent molecule). Preferably, the LSD1 inhibitor isadministered or formulated to be administered for 5 or more days to theindividual, more preferably from 5 days to 4 years, even more preferablyfrom 5 days to two years, yet even more preferably for 15 days to 2years, and again yet even more preferably from 15 days to 1 year. It isnoted that in this context administration for e.g., 5 or more days,means an amount sufficient over a time sufficient to cause pharmacologicinhibition of LSD1 over this period of time and this does notnecessarily mean administration of compound every day or only once perday. Depending on the PK/ADME properties of the inhibitors, a suitableamount and dosing regimen can be determined by a skilled practitioner inview of this disclosure.

In one aspect, the invention is a method of treating or preventing HCVcomprising identifying an individual in need of such treatment andadministering to said individual for a sufficient period of time anamount of a dual LSD1/MAOB inhibitor sufficient to treat or prevent HCV.In a related aspect, the invention is the use of a dual LSD1/MAOBinhibitor or a pharmaceutical composition comprising said dual LSD1/MAOBinhibitor in an amount sufficient to modulate LSD1 activity for treatingor preventing HCV. In a specific aspect, treating or preventing HCVcomprises inhibiting HCV RNA replication. In one embodiment of thisaspect, the amount of selective LSD1 inhibitor administered or that isin the pharmaceutical composition is sufficient to inhibit LSD1 and MAOBactivity while not substantially inhibiting MAOA activity, therebyavoiding or reducing side-effects associated with administration of MAOAinhibitors. In a specific aspect of this embodiment, preferably theamount of LSD1/MAOB inhibitor administered per day to a human is fromabout 0.5 mg to about 500 mg per day. More preferably, the amount ofLSD1/MAOB inhibitor administered per day to a human is from about 0.5 mgto about 200 mg per day or is a pharmaceutical composition formulated insuch a way as to deliver this amount of free base equivalent (or freeacid equivalent depending on the parent molecule). In one embodiment ofthis aspect, the amount of LSD1/MAOB inhibitor administered issufficient to inhibit LSD1/MAOB activity while not substantiallyinhibiting MAOA activity, thereby avoiding or reducing side-effectsassociated with administration of MAOA inhibitors. Preferably, the dualLSD1/MAOB inhibitor is administered or formulated to be administered for5 or more days to the individual, more preferably from 5 days to 4years, even more preferably from 5 days to two years, yet even morepreferably for 15 days to 2 years, and again yet even more preferablyfrom 15 days to 1 year. It is noted that in this context administrationfor e.g., 5 or more days, means an amount sufficient over a timesufficient to cause pharmacologic inhibition of LSD1 and MAOB over thisperiod of time and this does not necessarily mean administration ofcompound every day or only once per day. Depending on the PK/ADMEproperties of the inhibitors, a suitable amount and dosing regimen canbe determined by a skilled practitioner in view of this disclosure.

In one aspect, the invention is a method of treating or preventing HCVcomprising identifying an individual in need of such treatment andadministering to said individual for a sufficient period of time anamount of a LSD1 inhibitor and an interferon agent sufficient to treator prevent HCV. In a related aspect, the invention is the use of a LSD1inhibitor, or a pharmaceutical composition comprising said LSD1inhibitor, and an interferon agent, or a pharmaceutical compositioncomprising said interferon agent, in an amount sufficient for treatingor preventing HCV. In a specific aspect, treating or preventing HCVcomprises inhibiting HCV RNA replication via LSD1 and inhibiting HCV viaan interferon dependent mechanism. In one embodiment of this aspect, theamount of interferon administered to the individual is sufficient totreat or prevent HCV while avoiding or reducing side-effects associatedwith administration of higher doses of interferon. In a specific aspectof this embodiment, preferably the amount of LSD1 administered per dayto a human is from about 0.5 mg to about 500 mg per day. More preferablythe amount of LSD1 inhibitor administered per day to a human is fromabout 0.5 mg to about 200 mg per day or is a pharmaceutical compositionformulated in such a way as to deliver this amount of free baseequivalent (or free acid equivalent depending on the parent molecule).In one embodiment of this aspect, the amount of the interferon agentadministered to the individual is sufficient to treat or prevent HCV.More preferably, the amount of the interferon agent administered to theindividual is sufficient to treat or prevent HCV while avoiding orlessening the side effects associated with higher doses of an interferonagent. Depending on the PK/ADME properties of the inhibitors andinterferon agent a suitable amount and dosing regimen can be determinedby a skilled practitioner in view of this disclosure.

In one aspect, the invention is a method of treating or preventing HCVcomprising identifying a individual in need of such treatment andadministering to said individual for a sufficient period of time anamount of a LSD1 inhibitor and a protease inhibitor sufficient to treator prevent HCV. In a related aspect, the invention relates to a LSD1inhibitor, or a pharmaceutical composition comprising said LSD1inhibitor, and a protease inhibitor, or a pharmaceutical compositioncomprising said protease inhibitor, in an amount sufficient for use intreating or preventing HCV. In a specific aspect, treating or preventingHCV comprises inhibiting HCV RNA replication via LSD1 and inhibiting HCVvia a protease dependent mechanism. In one embodiment of this aspect,the amount of protease administered is sufficient to prevent or treatHCV. In one embodiment of this aspect, the amount of proteaseadministered is sufficient to prevent or treat HCV while avoiding orreducing side-effects associated with administration of higher doses ofprotease inhibitor. In one aspect, the protease inhibitor is Telaprevir,Boceprevir, TMC435350, R7227, VX985, MK7009 (Vaniprevir) or BI201335. Ina specific aspect of this embodiment, preferably the amount of LSD1administered per day to a human is from about 0.5 mg to about 500 mg perday. More preferably the amount of LSD1 inhibitor administered per dayto a human is from about 0.5 mg to about 200 mg per day or is apharmaceutical composition formulated in such a way as to deliver thisamount of free base equivalent (or free acid equivalent depending on theparent molecule). In one embodiment of this aspect, the amount of theprotease inhibitor administered to the individual is from 100 to 3000 mgdaily. More preferably, the amount of the protease inhibitor isadministered to the individual is from 100 to 2500 mg daily. Even morepreferably, the amount of the protease inhibitor administered to theindividual is from 100 to 2000 mg daily. Depending on the PK/ADMEproperties of the inhibitors, a suitable amount and dosing regimen canbe determined by a skilled practitioner in view of this disclosure.

In one aspect, the invention is a method of treating or preventing HCVcomprising identifying a individual in need of such treatment andadministering to said individual for a sufficient period of time anamount of a LSD1 inhibitor and a nucleoside polymerase inhibitorsufficient to treat or prevent HCV. In a related aspect, the inventionis the use of a LSD1 inhibitor, or a pharmaceutical compositioncomprising said LSD1 inhibitor, and nucleoside polymerase inhibitor, ora pharmaceutical composition comprising said nucleoside polymeraseinhibitor, in an amount sufficient for treating or preventing HCV. In aspecific aspect, treating or preventing HCV comprises inhibiting HCV RNAreplication via LSD1 and inhibiting HCV via a nucleoside polymerasedependent mechanism. In one embodiment of this aspect, the amount ofnucleoside polymerase inhibitor administered is sufficient to treat orprevent HCV. In one embodiment of this aspect, the amount of nucleosidepolymerase inhibitor administered is sufficient to treat or prevent HCVwhile avoiding or reducing side-effects associated with administrationof higher doses of nucleoside polymerase inhibitor. In one aspect, thenucleoside polymerase inhibitor is BI-207127, MK0608, R7128, PSI-7851,or IDX184. In a specific aspect of this embodiment, preferably theamount of LSD1 administered per day to a human is from about 0.5 mg toabout 500 mg per day. More preferably the amount of LSD1 inhibitoradministered per day to a human is from about 0.5 mg to about 200 mg perday or is a pharmaceutical composition formulated in such a way as todeliver this amount of free base equivalent (or free acid equivalentdepending on the parent molecule). In one embodiment of this aspect, theamount of the nucleoside polymerase inhibitor administered to theindividual is from 50 to 3000 mg per day. More preferably, the amount ofthe nucleoside polymerase inhibitor is administered to the individual isfrom 50 to 2250 mg per day. Even more preferably, the amount of thenucleoside polymerase inhibitor administered to the individual is from50 to 1500 mg per day. Depending on the PK/ADME properties of theinhibitors, a suitable amount and dosing regimen can be determined by askilled practitioner in view of this disclosure.

In one aspect, the invention is a method of treating or preventing HCVcomprising identifying an individual in need of such treatment andadministering to said individual for a sufficient period of time anamount of a LSD1 inhibitor and a non-nucleoside polymerase inhibitorsufficient to treat or prevent HCV. In a related aspect, the inventionis the use of a LSD1 inhibitor, or a pharmaceutical compositioncomprising said LSD1 inhibitor, and non-nucleoside polymerase inhibitor,or a pharmaceutical composition comprising said non-nucleosidepolymerase inhibitor, in an amount sufficient for treating or preventingHCV. In a specific aspect, treating or preventing HCV comprisesinhibiting HCV RNA replication via LSD1 and inhibiting HCV via anucleoside polymerase dependent mechanism. In one embodiment of thisaspect, the amount of non-nucleoside polymerase inhibitor administeredis sufficient to treat or prevent HCV. In one embodiment of this aspect,the amount of non-nucleoside polymerase inhibitor administered issufficient to treat or prevent HCV while avoiding or reducingside-effects associated with administration of higher doses ofnon-nucleoside polymerase inhibitor. In one aspect, the non-nucleosidepolymerase inhibitor is chosen from VX222, ANA598, GS9190, VCH759,PF-868554, ABT072, ABT333, or GL59728. In a specific aspect of thisembodiment, preferably the amount of LSD1 administered per day to ahuman is from about 0.5 mg to about 500 mg per day. More preferably theamount of LSD1 inhibitor administered per day to a human is from about0.5 mg to about 200 mg per day or is a pharmaceutical compositionformulated in such a way as to deliver this amount of free baseequivalent (or free acid equivalent depending on the parent molecule).In one embodiment of this aspect, the amount of the non-nucleosidepolymerase inhibitor administered to the individual is from 50 to 3000mg per day. More preferably, the amount of the non-nucleoside polymeraseinhibitor is administered to the individual is from 50 to 2250 mg perday. Even more preferably, the amount of the non-nucleoside polymeraseinhibitor administered to the individual is from 50 to 1500 mg per day.Depending on the PK/ADME properties of the inhibitors, a suitable amountand dosing regimen can be determined by a skilled practitioner in viewof this disclosure.

In one aspect, the invention is a method of treating or preventing HCVcomprising identifying an individual in need of such treatment andadministering to said individual for a sufficient period of time anamount of a LSD1 inhibitor and a NS5A inhibitor sufficient to treat orprevent HCV. In a related aspect, the invention is the use of a LSD1inhibitor, or a pharmaceutical composition comprising said LSD1inhibitor, and NS5A inhibitor, or a pharmaceutical compositioncomprising said NS5A inhibitor, in an amount sufficient for treating orpreventing HCV. In a specific aspect, treating or preventing HCVcomprises inhibiting HCV RNA replication via LSD1 and inhibiting HCV viaa NS5A dependent mechanism. In one embodiment of this aspect, the amountof NS5A inhibitor administered is sufficient to treat or prevent HCV. Inone embodiment of this aspect, the amount of NS5A inhibitor administeredis sufficient to treat or prevent HCV while avoiding or reducingside-effects associated with administration of higher doses of NS5Ainhibitor. In one aspect, the NS5A inhibitor is BMS-790052. In aspecific aspect of this embodiment, preferably the amount of LSD1administered per day to a human is from about 0.5 mg to about 500 mg perday. More preferably the amount of LSD1 inhibitor administered per dayto a human is from about 0.5 mg to about 200 mg per day or is apharmaceutical composition formulated in such a way as to deliver thisamount of free base equivalent (or free acid equivalent depending on theparent molecule). In one embodiment of this aspect, the amount of theNS5A inhibitor administered to the individual is from 50 to 3000 mg perday. More preferably, the amount of the NS5A inhibitor is administeredto the individual is from 50 to 2250 mg per day. Even more preferably,the amount of the NS5A inhibitor administered to the individual is from50 to 1500 mg per day. Depending on the PK/ADME properties of theinhibitors, a suitable amount and dosing regimen can be determined by askilled practitioner in view of this disclosure.

In one aspect, the invention relates to treating or preventing a diseaseor disorder associated with co-infection of HBV and HCV comprisingidentifying a patient co-infected or suspected of being co-infected withHBV and HCV and administering to said patient a therapeuticallyeffective amount of an LSD1 inhibitor and one or more anti-HCV oranti-HBV agents. One preferred anti-HCV or anti-HBV agent is aninterferon agent. Other anti-HBV agents include Lamivudine, AdefovirDipivoxil, Entecavir, Telbivudine, or Tenofovir. In one aspect, thesecond anti-HBV agent is Lamivudine, Adefovir Dipivoxil, Entecavir,Telbivudine, or Tenofovir. Other anti-HCV agents include proteaseinhibitors, nucleoside polymerase inhibitors, non-nucleoside polymeraseinhibitors, and NS5A inhibitors as described herein. While not wishingto be bound by theory, it is believed that treatment of HCV and HBVco-infection with an LSD1 inhibitor according to the invention yieldsunexpected benefits.

The invention also relates to an LSD1 inhibitor for use in any of theabove-described methods.

Accordingly, the invention relates to an LSD1 inhibitor (or apharmaceutical composition comprising an LSD1 inhibitor and apharmaceutically acceptable carrier) for use in treating or preventing aFlaviviridae infection. In one embodiment, the Flaviviridae is HepatitisC Virus, Yellow fever virus, West Nile Virus, Dengue Virus or Japaneseencephalitis virus. In a specific embodiment, the Flaviviridae is HCV,Dengue virus or West Nile virus. In another specific embodiment, theFlaviviridae is HCV. In another specific embodiment, the Flaviviridae isWNV. In another specific embodiment, the Flaviviridae is Dengue virus.In another specific embodiment, the Flaviviridae is yellow fever virus.In one aspect, the LSD1 inhibitor is a small molecule inhibitor of LSD1.In one aspect, the LSD1 inhibitor is a selective inhibitor of LSD1. Inone aspect, the LSD1 inhibitor is a selective inhibitor of LSD1 and MAOB(i.e. a dual LSD1/MAO-B inhibitor). In one aspect, the LSD1 inhibitor isa 2-cyclylcyclopropan-1-amine compound, a phenelzine compound, or apropargylamine compound, more preferably a 2-cyclylcyclopropan-1-aminecompound, still more preferably a 2-arylcyclopropan-1-amine compound ora 2-heteroarylcyclopropan-1-amine compound, and even more preferably a2-phenylcyclopropan-1-amine compound, 2-pyridinylcyclopropan-1-aminecompound or a 2-thiazolylcyclopropan-1-amine compound. In one aspect ofthis embodiment, the LSD1 inhibitor has a therapeutic index of 10 orgreater. In one aspect of this embodiment, the LSD1 inhibitor has atherapeutic index of 50 or greater. In one aspect of this embodiment,the LSD1 inhibitor has a therapeutic index of 100 or greater.

The invention also relates to an LSD1 inhibitor (or a pharmaceuticalcomposition comprising an LSD1 inhibitor and a pharmaceuticallyacceptable carrier) for use in inhibiting Flaviviridae RNA replication.In one embodiment, the Flaviviridae is Hepatitis C Virus, Yellow fevervirus, West Nile Virus, Dengue Virus or Japanese encephalitis virus. Ina specific embodiment, the Flaviviridae is HCV, Dengue virus or WestNile virus. In another specific embodiment, the Flaviviridae is HCV. Inanother specific embodiment, the Flaviviridae is WNV. In anotherspecific embodiment, the Flaviviridae is Dengue virus. In anotherspecific embodiment, the Flaviviridae is yellow fever virus. In oneaspect, the LSD1 inhibitor is a small molecule inhibitor of LSD1. In oneaspect, the LSD1 inhibitor is a selective inhibitor of LSD1. In oneaspect, the LSD1 inhibitor is a selective inhibitor of LSD1 and MAOB(i.e. a dual LSD1/MAO-B inhibitor). In one aspect, the LSD1 inhibitor isa 2-cyclylcyclopropan-1-amine compound, a phenelzine compound, or apropargylamine compound, more preferably a 2-cyclylcyclopropan-1-aminecompound, still more preferably a 2-arylcyclopropan-1-amine compound ora 2-heteroarylcyclopropan-1-amine compound, and even more preferably a2-phenylcyclopropan-1-amine compound, 2-pyridinylcyclopropan-1-aminecompound or a 2-thiazolylcyclopropan-1-amine compound, or apropargylamine derivative or analog. In one aspect of this embodiment,the LSD1 inhibitor has a therapeutic index of 10 or greater. In oneaspect of this embodiment, the LSD1 inhibitor has a therapeutic index of50 or greater. In one aspect of this embodiment, the LSD1 inhibitor hasa therapeutic index of 100 or greater.

Likewise, the invention encompasses an LSD1 inhibitor (or apharmaceutical composition comprising an LSD1 inhibitor and apharmaceutically acceptable carrier) for use in treating or preventingHCV infection. In one aspect, the LSD1 inhibitor is a small moleculeinhibitor of LSD1. In one aspect, the LSD1 inhibitor is a selectiveinhibitor of LSD1. In one aspect, the LSD1 inhibitor is a selectiveinhibitor of LSD1 and MAOB (i.e. a dual LSD1/MAO-B inhibitor). In oneaspect, the LSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound, aphenelzine compound, or a propargylamine compound, more preferably a2-cyclylcyclopropan-1-amine compound, still more preferably a2-arylcyclopropan-1-amine compound or a 2-heteroarylcyclopropan-1-aminecompound, and even more preferably a 2-phenylcyclopropan-1-aminecompound, 2-pyridinylcyclopropan-1-amine compound or a2-thiazolylcyclopropan-1-amine compound. In one aspect of thisembodiment, the LSD1 inhibitor has a therapeutic index of 10 or greater.In one aspect of this embodiment, the LSD11 inhibitor has a therapeuticindex of 50 or greater. In one aspect of this embodiment, the LSD1inhibitor has a therapeutic index of 100 or greater.

The invention also relates to an LSD1 inhibitor (or a pharmaceuticalcomposition comprising an LSD1 inhibitor and a pharmaceuticallyacceptable carrier) for use in inhibiting HCV RNA replication. In oneaspect, the LSD1 inhibitor is a small molecule inhibitor of LSD1. In oneaspect, the LSD1 inhibitor is a selective inhibitor of LSD1. In oneaspect, the LSD1 inhibitor is a selective inhibitor of LSD1 and MAOB(i.e. a dual LSD1/MAO-B inhibitor). In one aspect, the LSD1 inhibitor isa 2-cyclylcyclopropan-1-amine compound, a phenelzine compound, or apropargylamine compound, more preferably a 2-cyclylcyclopropan-1-aminecompound, still more preferably a 2-arylcyclopropan-1-amine compound ora 2-heteroarylcyclopropan-1-amine compound, and even more preferably a2-phenylcyclopropan-1-amine compound, 2-pyridinylcyclopropan-1-aminecompound or a 2-thiazolylcyclopropan-1-amine compound. In one aspect ofthis embodiment, the LSD1 inhibitor has a therapeutic index of 10 orgreater. In one aspect of this embodiment, the LSD1 inhibitor has atherapeutic index of 50 or greater. In one aspect of this embodiment,the LSD1 inhibitor has a therapeutic index of 100 or greater.

Moreover, the invention encompasses an LSD1 inhibitor (or apharmaceutical composition comprising an LSD1 inhibitor and apharmaceutically acceptable carrier) for use in the treatment orprevention of liver disease in an individual infected with HCV. In apreferred embodiment, the liver disease is hepatitis or hepatocellularcarcinoma. In one aspect, the LSD1 inhibitor is a small moleculeinhibitor of LSD1. In one aspect, the LSD1 inhibitor is a selectiveinhibitor of LSD1. In one aspect, the LSD1 inhibitor is a selectiveinhibitor of LSD1 and MAOB (i.e. a dual LSD1/MAO-B inhibitor). In oneaspect, the LSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound, aphenelzine compound, or a propargylamine compound, more preferably a2-cyclylcyclopropan-1-amine compound, still more preferably a2-arylcyclopropan-1-amine compound or a 2-heteroarylcyclopropan-1-aminecompound, and even more preferably a 2-phenylcyclopropan-1-aminecompound, 2-pyridinylcyclopropan-1-amine compound or a2-thiazolylcyclopropan-1-amine compound. In one aspect of thisembodiment, the LSD1 inhibitor has a therapeutic index of 10 or greater.In one aspect of this embodiment, the LSD1 inhibitor has a therapeuticindex of 50 or greater. In one aspect of this embodiment, the LSD1inhibitor has a therapeutic index of 100 or greater.

The invention also relates to a LSD1 inhibitor (or a pharmaceuticalcomposition comprising an LSD1 inhibitor and a pharmaceuticallyacceptable carrier) and one or more further therapeutic agents for usein the treatment or prevention of a Flaviviridae infection or a diseasecaused by Flaviviridae. In one aspect, the invention provides a LSD1inhibitor (or a pharmaceutical composition comprising an LSD1 inhibitorand a pharmaceutically acceptable carrier) and a second anti-HCV agentfor use in the treatment or prevention of HCV infection or a diseasecaused by HCV. In one embodiment, the second anti-HCV agent is chosenfrom an interferon agent, a nucleoside polymerase inhibitor, anon-nucleoside polymerase inhibitor, a protease inhibitor or a NS5Ainhibitor. In one embodiment, the second anti-HCV agent is an interferonagent. In one embodiment, the second anti-HCV agent is a nucleosidepolymerase inhibitor. In a specific embodiment the nucleoside polymeraseinhibitor is BI-207127, MK0608, R7128, PSI-7851, or IDX184 In oneembodiment, the second anti-HCV agent is a non-nucleoside polymeraseinhibitor. In a specific embodiment the non-nucleoside polymeraseinhibitor is chosen from VX222, ANA598, GS9190, VCH759, PF-868554,ABT072, ABT333, or GL59728. In one embodiment, the second anti-HCV agentis a protease inhibitor. In a specific embodiment, the proteaseinhibitor is Telaprevir, Boceprevir, TMC435350, R7227, VX985, MK7009(Vaniprevir) or BI1201335. In one embodiment, the second anti-HCV agentis a NS5A inhibitor. In a specific embodiment, the NS5A inhibitor isBMS-790052. In one aspect, the LSD1 inhibitor is a small moleculeinhibitor of LSD1. In one aspect, the LSD1 inhibitor is a selectiveinhibitor of LSD1. In one aspect, the LSD1 inhibitor is a selectiveinhibitor of LSD1 and MAOB (i.e. a dual LSD1/MAO-B inhibitor). In oneaspect, the LSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound, aphenelzine compound, or a propargylamine compound, more preferably a2-cyclylcyclopropan-1-amine compound, still more preferably a2-arylcyclopropan-1-amine compound or a 2-heteroarylcyclopropan-1-aminecompound, and even more preferably a 2-phenylcyclopropan-1-aminecompound, 2-pyridinylcyclopropan-1-amine compound or a2-thiazolylcyclopropan-1-amine compound. In one aspect of thisembodiment, the LSD1 inhibitor has a therapeutic index of 10 or greater.In one aspect of this embodiment, the LSD1 inhibitor has a therapeuticindex of 50 or greater. In one aspect of this embodiment, the LSD1inhibitor has a therapeutic index of 100 or greater.

In one embodiment, the protease inhibitor is Telaprevir, Boceprevir,TMC435350, R7227, or BI201335. In another embodiment, the nucleosidepolymerase inhibitor is R7128, PSI-7851, or IDX184. In anotherembodiment, the non-nucleoside polymerase inhibitor is PF-868554 orGS-9190. In another embodiment, the NS5A inhibitor is BMS-790052.

Compounds, Formulation, and Routes of Administration

The LSD1 inhibitors, in particular selective LSD1 inhibitors and dualLSD1/MAOB inhibitors for use in the invention can be synthesized by anumber of techniques including the ones that are described below.

Examples of selective LSD1 and LSD1/MAOB dual inhibitors are given ine.g., WO2010/043721 (PCT/EP2009/063685), WO2010/084160(PCT/EP2010/050697), WO 2011/035941 (PCT/EP2010/055131); WO2011/042217(PCT/EP2010/055103); WO2011/131697 (PCT/EP2011/056279),PCT/EP2011/062947, PCT/EP2011/067608, PCT/EP2011/062949 and EPapplication numbers EP10171345 all of which are explicitly incorporatedherein by reference in their entireties to the extent they are notinconsistent with the instant disclosure.

In one specific aspect, a phenylcyclopropylamine derivative or analogfor use in the invention is phenylcyclopropylamine (PCPA) with one ortwo substitutions on the amine group; phenylcyclopropylamine with zero,one or two substitutions on the amine group and one, two, three, four,or five substitution on the phenyl group; phenylcyclopropylamine withone, two, three, four, or five substitution on the phenyl group;phenylcyclopropylamine with zero, one or two substitutions on the aminegroup wherein the phenyl group of PCPA is substituted with (exchangedfor) another ring system chosen from aryl or heterocyclyl or heteroarylto give an aryl- or heterocyclyl- or heteroaryl-cyclopropylamine havingzero, one or two substituents on the amine group; phenylcyclopropylaminewherein the phenyl group of PCPA is substituted with (exchanged for)another ring system chosen from aryl or heterocyclyl to give an aryl- orheterocycyl-cyclopropylamine wherein said aryl- orheterocyclyl-cyclopropylamine on said aryl or heterocyclyl moiety haszero, one or two substitutions on the amine group and one, two, three,four, or five substitution on the phenyl group; phenylcyclopropylaminewith one, two, three, four, or five substitution on the phenyl group; orany of the above described phenylcyclopropylamine analogs or derivativeswherein the cyclopropyl has one, two, three or four additionalsubstituents. Preferably, the heterocyclyl group described above in thisparagraph in a heteroaryl.

Other examples of LSD1 inhibitors are e.g., phenelzine or pargyline(propargylamine) or a derivative or analog thereof. Derivatives andanalogs of phenelzine and pargyline (propargylamine) include, but arenot limited to, compounds where the phenyl group of the parent compoundis replaced with a heteroaryl or optionally substituted cyclic group orthe phenyl group of the parent compound is optionally substituted with acyclic group. In one aspect, the phenelzine or pargyline derivative oranalog thereof has selective LSD1 or dual LSD1/MAOB inhibitory activityas described herein. In one aspect, the phenelzine derivative or analoghas one, two, three, four or five substituents on the phenyl group. Inone aspect, the phenelzine derivative or analog has the phenyl groupsubstituted with (exchanged for) an aryl or heterocyclyl group whereinsaid aryl or heterocyclyl group has zero, one, two, three, four or fivesubstituents. In one aspect, the pargyline derivative or analog has one,two, three, four or five substituents on the phenyl group. In oneaspect, the pargyline derivative or analog has the phenyl groupsubstituted with (exchanged for) an aryl or heterocyclyl group whereinsaid aryl or heterocyclyl group has zero, one, two, three, four or fivesubstituents. Methods of preparing such compounds are known to theskilled artisan.

The LSD1 inhibitor or selective LSD1 inhibitor or dual LSD1/MAO-Binhibitor to be used in accordance with the present invention ispreferably a 2-cyclylcyclopropan-1-amine compound, a phenelzine compoundor a propargylamine compound, and is more preferably a2-cyclylcyclopropan-1-amine compound. Said 2-cyclylcyclopropan-1-aminecompound is preferably a 2-arylcyclopropan-1-amine compound or a2-heteroarylcyclopropan-1-amine compound, more preferably a2-phenylcyclopropan-1-amine compound, a 2-pyridinylcyclopropan-1-aminecompound or a 2-thiazolylcyclopropan-1-amine compound.

It is particularly preferred that the LSD1 inhibitor or selective LSD1inhibitor or dual LSD1/MAO-B inhibitor is a 2-cyclylcyclopropan-1-aminecompound which is a compound of the following formula (I) or anenantiomer, a diastereomer, or a racemic mixture thereof, or apharmaceutically acceptable salt or solvate thereof:

A is cyclyl optionally having 1, 2, 3 or 4 substituents A′. Preferably,said cyclyl is aryl or heteroaryl. Said aryl is preferably phenyl. Saidheteroaryl is preferably selected from pyridinyl, pyrimidinyl,thiophenyl, benzothiophenyl, pyrrolyl, indolyl, furanyl or thiazolyl,more preferably said heteroaryl is selected from pyridinyl, pyrimidinylor thiazolyl, still more preferably said heteroaryl is pyridinyl (inparticular, pyridin-2-yl or pyridin-3-yl) or thiazolyl (in particularthiazol-5-yl) and even more preferably said heteroaryl is pyridin-3-ylor thiazol-5-yl.

It is preferred that said cyclyl (or said aryl or said heteroaryl, orany of the above-mentioned specific aryl or heteroaryl groups) isunsubstituted or has 1 or 2 substituents A′, and it is more preferredthat said cyclyl (or said aryl or said heteroaryl, or any of theabove-mentioned specific aryl or heteroaryl groups) is unsubstituted orhas 1 substituent A′.

Said substituent(s) A′ is/are each independently selected from-L¹-cyclyl (e.g., -L¹-aryl, -L¹-cycloalkyl or -L¹-heterocyclyl), alkyl,alkenyl, alkynyl, alkoxy, amino, amido (e.g., —CO—NH₂), —CH₂—CO—NH₂,alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano,sulfonyl, sulfinyl, sulfonamide, acyl, carboxyl, carbamate or urea,wherein the cyclyl moiety comprised in said -L¹-cyclyl is optionallyfurther substituted with one or more (e.g., 1, 2 or 3) groupsindependently selected from halo, haloalkyl, haloalkoxy, aryl,arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino,amido (e.g., —CO—NH₂), alkylamino, hydroxyl, nitro, —CH₂—CO—NH₂,heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cyano,sulfonyl, sulfinyl, sulfonamide, acyl, carboxyl, carbamate or urea,preferably selected from halo, haloalkyl, N-sulfonamido or cyano. It ispreferred that the cyclyl moiety comprised in said -L¹-cyclyl isunsubstituted or is substituted with one of the above groups (including,e.g., one of the preferred groups halo, haloalkyl, N-sulfonamido orcyano). In one preferred embodiment, the cyclyl moiety comprised in said-L¹-cyclyl is substituted with one of the above groups (including, e.g.,one of the preferred groups halo, haloalkyl, N-sulfonamido or cyano). Inanother preferred embodiment the cyclyl moiety is unsubstituted. Said-L¹-cyclyl is preferably -L¹-aryl, -L¹-cycloalkyl or -L¹-heterocyclyl(e.g., -L¹-heteroaryl or -L¹-heterocycloalkyl), more preferably -L¹-arylor -L¹-heteroaryl, even more preferably -L¹-aryl, even more preferably-L¹-phenyl.

Each L¹ is independently selected from a covalent bond, —(CH₂)₁₋₆—,—(CH₂)₀₋₃—O—(CH₂)₀₋₃—, —(CH₂)₀₋₃—NH—(CH₂)₀₋₃— or —(CH₂)₀₋₃—S—(CH₂)₀₋₃—,preferably from a covalent bond, —(CH₂)₁₋₃—, —O—(CH₂)₀₋₃— or—NH—(CH₂)₀₋₃—, more preferably from a covalent bond, —CH₂—, —O—,—O—CH₂—, —O—(CH₂)₂—, —NH— or —NH—CH₂—, even more preferably from acovalent bond, —CH₂— or —O—CH₂—. It is furthermore preferred that theaforementioned groups L¹ (connecting the moiety A to the cyclyl moietycomprised in -L¹-cyclyl) are in the specific orientation indicated above(accordingly, the group “—O—CH₂-” as an example for L¹ is preferably inthe orientation ( . . . )-A-O—CH₂-cyclyl).

Preferably, said substituent(s) A′ is/are each independently selectedfrom -L¹-aryl, -L¹-cycloalkyl, -L¹-heteroaryl or -L¹-heterocycloalkyl,wherein said aryl, said cycloalkyl, said heteroaryl or saidheterocycloalkyl is optionally substituted with halo (e.g., —F or —Cl),haloalkyl (e.g., —CF₃), N-sulfonamido (e.g. —NHSO₂-aryl, wherein thearyl group can be optionally substituted) or cyano. More preferably,said substituent(s) A′ is/are each independently -L¹-aryl (e.g.,-L¹-phenyl), wherein the aryl moiety in said -L¹-aryl (or the phenylmoiety in said -L¹-phenyl) is optionally substituted with halo (e.g., —For —Cl), haloalkyl (e.g., —CF₃), N-sulfonamido (e.g. —NHSO₂-aryl,wherein the aryl group can be optionally substituted) or cyano. Evenmore preferably, said substituent(s) A′ is/are each independentlyphenyl, —CH₂-phenyl, —O—CH₂-phenyl, —NH—CH₂-phenyl or —O—(CH₂)₂-phenyl,wherein said phenyl or the phenyl moiety in said —CH₂-phenyl, said—O—CH₂-phenyl, said —NH—CH₂-phenyl or said —O—(CH₂)₂-phenyl isoptionally substituted with halo (e.g., —F or —Cl), haloalkyl (e.g.,—CF₃), N-sulfonamido (e.g. —NHSO₂-aryl, wherein the aryl group can beoptionally substituted) or cyano. Even more preferably, saidsubstituent(s) A′ is/are each independently phenyl, —CH₂-phenyl, or—O—CH₂-phenyl, wherein said phenyl or the phenyl moiety in said—CH₂-phenyl or said —O—CH₂-phenyl is optionally substituted with halo(e.g., —F or —Cl) or haloalkyl (e.g., —CF₃).

It is particularly preferred that A is aryl (preferably phenyl) orheteroaryl (preferably pyridinyl or thiazolyl), which aryl or heteroaryloptionally has one substituent A′ selected from -L¹-aryl,-L¹-cycloalkyl, -L¹-heteroaryl or -L¹-heterocycloalkyl (wherein the arylmoiety in said -L¹-aryl, the cycloalkyl moiety in said -L¹-cycloalkyl,the heteroaryl moiety in said -L¹-heteroaryl or the heterocycloalkylmoiety in said -L¹-heterocycloalkyl may be substituted with halo (e.g.,—F or —Cl), haloalkyl (e.g., —CF₃) or cyano), preferably selected fromphenyl, —CH₂-phenyl or —O—CH₂-phenyl (wherein said phenyl, the phenylmoiety in said —CH₂-phenyl or the phenyl moiety in said —O—CH₂-phenylmay be substituted with halo (e.g., —F or —Cl) or haloalkyl (e.g.,—CF₃)).

B is —H, -L²-CO—NH₂, -L²-CO—NR¹R², -L²-CO—R³ or -L²-cyclyl, wherein thecyclyl moiety in said -L²-cyclyl is optionally substituted with one ormore (e.g., one, two or three) groups independently selected from halo,haloalkyl, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl,alkyl, alkenyl, alkynyl, alkoxy, amino, amido (e.g., —CO—NH₂),alkylamino, hydroxyl, nitro, —CH₂—CO—NH₂, heteroaryl, heteroarylalkoxy,heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkylalkoxy,cycloalkoxy, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy,heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato,thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide,trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio,cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio,carboxyl, carbamate or urea, preferably selected from halo, alkyl,alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, amino, alkylamino,aminoalkyl, amido (e.g., —CO—NH₂), —CH₂—CO—NH₂, or sulfonamide.

It is preferred that the cyclyl moiety in said -L²-cyclyl isunsubstituted or is substituted with one group selected from halo,haloalkyl, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl,alkyl, alkenyl, alkynyl, alkoxy, amino, amido (e.g., —CO—NH₂),alkylamino, hydroxyl, nitro, —CH₂—CO—NH₂, heteroaryl, heteroarylalkoxy,heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkylalkoxy,cycloalkoxy, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy,heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato,thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide,trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio,cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio,carboxyl, carbamate or urea, preferably selected from halo, alkyl,alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, amino, alkylamino,aminoalkyl, amido (e.g., —CO—NH₂), —CH₂—CO—NH₂, or sulfonamide.

The cyclyl moiety in said -L²-cyclyl, which may be substituted asdefined and described above, is preferably selected from aryl,cycloalkyl or heterocyclyl (e.g., heteroaryl or heterocycloalkyl), morepreferably from cycloalkyl or heterocyclyl, still more preferably fromheterocyclyl, even more preferably from heteroaryl or heterocycloalkyl.Said heteroaryl is preferably selected from oxadiazolyl, thiazolyl orpyrimidinyl. Said heterocycloalkyl is preferably selected frompyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl ormorpholinyl.

In formula (I), R¹ and R² are each independently chosen from —H, alkyl,alkynyl, alkenyl, -L-carbocycle, -L-aryl, -L-heterocyclyl, wherein saidalkyl, said alkynyl or said alkenyl is optionally substituted with oneor more groups independently selected from halo, haloalkoxy, haloaryl,aryl, arylalkoxy, aryloxy, alkoxy, amino, amido, alkylamino, hydroxyl,nitro, —CH₂—CO—NH₂, heteroaryl, heteroarylalkoxy, heteroaryloxy,cycloalkyl, cycloalkylalkoxy, cycloalkoxy, heterocycloalkyl,heterocycloalkylalkoxy, heterocycloalkoxy, cyano, cyanato, isocyanato,thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide,trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio,cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio,carboxyl, carbamate or urea, and further wherein the carbocycle moietyin said -L-carbocycle, the aryl moiety in said -L-aryl, or theheterocyclyl moiety in said -L-heterocyclyl is optionally substitutedwith one or more groups independently selected from halo, haloalkyl,haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl,alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl, nitro,—CH₂—CO—NH₂, heteroaryl, heteroarylalkoxy, heteroaryloxy,heteroarylalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkoxy,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy,heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato,thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide,trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio,cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio,carboxyl, carbamate or urea.

In formula (I), R³ is chosen from —H, alkoxy, -L-carbocyclic,-L-heterocyclic, -L-aryl, wherein the carbocyclic moiety in said-L-carbocyclic, the heterocyclic moiety in said -L-heterocyclic or thearyl moiety in said -L-aryl is optionally substituted with one or moregroups independently selected from halo, haloalkyl, haloalkoxy,haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl,alkoxy, amino, amido, alkylamino, hydroxyl, nitro, —CH₂—CO—NH₂,heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl,cycloalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy,heterocycloalkylalkyl, cyano, cyanato, isocyanato, thiocyanato,isothiocyanato, sulfonyl, sulfinyl, sulfonamide,trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio,cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio,carboxyl, carbamate or urea. R³ is preferably -L-heterocyclic, and morepreferably -L-heterocycloalkyl, wherein the heterocyclic moiety in said-L-heterocyclic or the heterocycloalkyl moiety in said-L-heterocycloalkyl is optionally substituted, as defined above. Evenmore preferably, R³ is -L-heterocycloalkyl, wherein the heterocycloalkylmoiety comprised in said -L-heterocycloalkyl is selected frompyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl ormorpholinyl, and is optionally substituted as defined above. Theoptional substituents in R³ are preferably selected from halo, alkyl,alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, amino, alkylamino,aminoalkyl, amido (e.g., —CO—NH₂), —CH₂—CO—NH₂, or sulfonamide.

Each L is independently selected from —(CH₂)_(n)—(CH₂)_(n)—,—(CH₂)_(n)C(═O)(CH₂)_(n)—, —(CH₂)_(n)C(═O)NH(CH₂)_(n)—,—(CH₂)_(n)NHC(═O)O(CH₂)_(n)—, —(CH₂)_(n)NHC(═O)NH(CH₂)_(n)—,—(CH₂)_(n)NHC(═S)S(CH₂)_(n)—, —(CH₂)_(n)OC(═O)S(CH₂)_(n)—,—(CH₂)_(n)NH(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(n)—, —(CH₂)_(n)S(CH₂)_(n)—,and —(CH₂)_(n)NHC(═S)NH(CH₂)_(n)—, and each n is independently chosenfrom 0, 1, 2, 3, 4, 5, 6, 7, and 8. Preferably, each L in R¹ and R² isindependently —(CH₂)₁₋₆—, more preferably —(CH₂)₁₋₄—, and even morepreferably CH₂—. Moreover, L in R³ is preferably a covalent bond or—(CH₂)₁₋₄—, more preferably a covalent bond or —(CH₂)₁₋₄—, and even morepreferably a covalent bond.

L² is C₁₋₁₂ alkylene which is optionally interrupted by one or more(e.g., one, two, three or four) groups independently selected from —O—,—S—, —NH—, —N(alkyl)-, —CO—, —CO—NH— or —CO—N(alkyl)-, or L² is acovalent bond. Preferably, L² is —CH₂—(C₁₋₆alkylene), —CH₂—CO— or acovalent bond, wherein the alkylene moiety in said —CH₂—(C₁₋₆ alkylene)is optionally interrupted by one or more (e.g., one, two or three)groups independently selected from —O—, —S—, —NH—, —N(alkyl)-, —CO—,—CO—NH—, —CO—N(alkyl)-. More preferably, L² is —(CH₂)₁₋₄—, —CH₂—CO— or acovalent bond. Even more preferably, L² is —CH₂—, —(CH₂)₂—, —CH₂—CO— ora covalent bond.

Preferably, B is —H, —(CH₂)₁₋₄—CO—NH₂, —(CH₂)₁₋₄—CO—NR¹R²,—(CH₂)₀₋₅-heteroaryl, —(CH₂)₀₋₅-heterocycloalkyl or—(CH₂)₁₋₅—CO-heterocycloalkyl, wherein the heteroaryl moiety comprisedin said —(CH₂)₀₋₅-heteroaryl or the heterocycloalkyl moiety comprised insaid —(CH₂)₀₋₅-heterocycloalkyl or in said —(CH₂)₁₋₅—CO-heterocycloalkylis optionally substituted with one group selected from halo, alkyl,alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, amino, alkylamino,aminoalkyl, amido (e.g., —CO—NH₂), —CH₂—CO—NH₂, or sulfonamide.

In a particularly preferred embodiment, B is —H. In a furtherparticularly preferred embodiment, B is —(CH₂)₁₋₄—CO—NH₂, morepreferably —CH₂—CO—NH₂. In a further particularly preferred embodiment,B is —(CH₂)₁₋₄—CO—NR¹R², more preferably —CH₂—CO—NR¹R². In a furtherparticularly preferred embodiment, B is —(CH₂)₀₋₅-heteroaryl, whereinthe heteroaryl moiety comprised in said —(CH₂)₀₋₅-heteroaryl ispreferably selected from oxadiazolyl, thiazolyl or pyrimidinyl and,furthermore, is optionally substituted with one group selected fromhalo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, amino,alkylamino, aminoalkyl, amido (e.g., —CO—NH₂), —CH₂—CO—NH₂, orsulfonamide. In a further particularly preferred embodiment, B is—(CH₂)₀₋₅-heterocycloalkyl, wherein the heterocycloalkyl moietycomprised in said —(CH₂)₀₋₅-heterocycloalkyl is preferably selected frompyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl ormorpholinyl and, furthermore, is optionally substituted with one groupselected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano,hydroxyl, amino, alkylamino, aminoalkyl, amido (e.g., —CO—NH₂),—CH₂—CO—NH₂, or sulfonamide. In a further particularly preferredembodiment, B is —CH₂-oxadiazolyl, wherein the oxadiazolyl moietycomprised in said —CH₂-oxadiazolyl is optionally substituted with onegroup selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano,hydroxyl, amino, alkylamino or aminoalkyl (accordingly, B may, forexample, be aminooxadiazolylmethyl, such as2-amino-1,3,4-oxadiazol-5-ylmethyl or3-amino-1,2,4-oxadiazol-5-ylmethyl). In a further particularly preferredembodiment, B is —(CH₂)₁₋₅—CO-heterocycloalkyl, wherein theheterocycloalkyl moiety comprised in said —(CH₂)₁₋₅—CO-heterocycloalkylis preferably selected from pyrrolidinyl, piperidinyl, piperazinyl,N-methylpiperazinyl or morpholinyl and, furthermore, is optionallysubstituted with one group selected from halo, alkyl, alkoxy, haloalkyl,haloalkoxy, cyano, hydroxyl, amino, alkylamino, aminoalkyl, amido (e.g.,—CO—NH₂), —CH₂—CO—NH₂, or sulfonamide.

The substituents on the cyclopropane ring, i.e. the groups -(A) and—NH—B, are preferably in trans configuration. In that case, the2-cyclylcyclopropan-1-amine compound of formula (I) may have theconfiguration (1R,2S) or the configuration (1S,2R) at the cyclopropanering carbon atoms. The present invention specifically relates to the(1R,2S) stereoisomer of the 2-cyclylcyclopropan-1-amine compound offormula (I). The invention also specifically relates to the (1S,2R)stereoisomer of the 2-cyclylcyclopropan-1-amine compound of formula (I)

In one embodiment, the LSD1 inhibitor or selective LSD1 inhibitor ordual LSD1/MAO-B inhibitor to be used in accordance with the presentinvention is a 2-cyclylcyclopropan-1-amine compound which is a compoundof the following formula (II) or a pharmaceutically acceptable saltthereof:

In formula (U), each of R1-R5 is optionally substituted andindependently chosen from —H, halo, alkyl, alkoxy, cycloalkoxy,haloalkyl, haloalkoxy, -L-aryl, -L-heteroaryl, -L-heterocyclyl,-L-carbocycle, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl,amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanato,trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, and C-amido;

R6 is chosen from —H and alkyl;

R7 is chosen from —H, alkyl, and cycloalkyl;

R8 is chosen from —C(═O)NR_(x)R_(y) and —C(═O)R_(z);

R_(x) when present is chosen from —H, alkyl, alkynyl, alkenyl,-L-carbocycle, -L-aryl, -L-heterocyclyl, all of which are optionallysubstituted;

R_(y) when present is chosen from —H, alkyl, alkynyl, alkenyl,-L-carbocycle, -L-aryl, -L-heterocyclyl, all of which are optionallysubstituted;

R_(z) when present is chosen from —H, alkoxy, -L-carbocyclic,-L-heterocyclic, -L-aryl, wherein the aryl, heterocyclyl, or carbocycleis optionally substituted;

each L can be saturated, partially saturated, or unsaturated, and isindependently chosen from —(CH₂)_(n)—(CH₂)_(n)—,—(CH₂)_(n)C(═O)(CH₂)_(n)—, —(CH₂)_(n)C(═O)NH(CH₂)_(n)—,—(CH₂)_(n)NHC(═O)O(CH₂)_(n)—, —(CH₂)_(n)NHC(═O)NH(CH₂)_(n)—,—(CH₂)_(n)NHC(═S)S(CH₂)_(n)—, —(CH₂)_(n)OC(═O)S(CH₂)_(n)—,—(CH₂)_(n)NH(CH₂)_(n)—, —(CH₂)_(n)—O—(CH₂)_(n)—, —(CH₂)_(n)S(CH₂)_(n)—,and —(CH₂)_(n)NHC(═S)NH(CH₂)_(n)—, where each n is independently chosenfrom 0, 1, 2, 3, 4, 5, 6, 7, and 8, wherein optionally substitutedrefers to zero or 1 to 4 optional substituents independently chosen fromacylamino, acyloxy, alkenyl, alkoxy, cycloalkoxy, alkyl, alkylthio,cycloalkylthio, alkynyl, amino, aryl, arylalkyl, arylalkenyl,arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, carbocyclyl,cyano, cyanato, halo, haloalkyl, haloaryl, hydroxyl, heteroaryl,heteroaryloxy, heterocyclyl, heteroarylalkoxy, isocyanato,isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl,thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, and C-amido.

In a further embodiment, the LSD1 inhibitor or selective LSD1 inhibitoror dual LSD1/MAO-B inhibitor to be used in accordance with the inventionis a 2-cyclylcyclopropan-1-amine compound which is a compound of thefollowing formula (III) or a pharmaceutically acceptable salt thereof:

In formula (III), each of R1-R5 is independently chosen from —H, halo,alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio,cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido;

R6 is chosen from —H and alkyl;

R7 is chosen from —H, alkyl, and cycloalkyl;

R8 is a -L-heterocyclyl wherein the ring or ring system of said-L-heterocyclyl has from 0-3 substituents chosen from halo, alkyl,alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl,amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl,arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato,nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, and C-amido; or

R8 is -L-aryl wherein the ring or ring system of said -L-aryl has from1-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, and C-amido;

each L is independently chosen from —(CH₂)_(n)—(CH₂)_(n)—,—(CH₂)_(n)NH(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(n)—, and—(CH₂)_(n)S(CH₂)_(n)—, and where each n is independently chosen from 0,1, 2, and 3.

In a further embodiment, the LSD1 inhibitor or selective LSD1 inhibitoror dual LSD1/MAO-B inhibitor to be used in accordance with the inventionis a 2-cyclylcyclopropan-1-amine compound which is a compound of thefollowing formula (IV) or an enantiomer, diastereomer, or mixturethereof, or a pharmaceutically acceptable salt or solvate thereof:

(A′)_(X)-(A)-(B)—(Z)-(L)-(D)  (IV)

In formula (IV), (A) is heteroaryl or aryl;

each (A′), if present, is independently chosen from aryl, arylalkoxy,arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyl, cycloalkyl,haloalkoxy, and cyano, wherein each (A′) is substituted with 0, 1, 2, or3 substituents independently chosen from halo, haloalkyl, aryl,arylalkoxy, alkyl, alkoxy, cyano, sulfonyl, amido, and sulfinyl;

X is 0, 1, 2, or 3;

(B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded todifferent carbon atoms of (B);

(Z) is —NH—;

(L) is chosen from —CH₂CH₂—, —CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂—; and

(D) is chosen from —N(—R1)-R2, —O—R3, and —S—R3, wherein:

R1 and R2 are mutually linked to form a heterocyclic ring together withthe nitrogen atom that R1 and R2 are attached to, wherein saidheterocyclic ring has 0, 1, 2, or 3 substituents independently chosenfrom —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆ alkyl), alkyl, halo,cyano, alkoxy, haloalkyl, and haloalkoxy, or

R1 and R2 are independently chosen from —H, alkyl, cycloalkyl,haloalkyl, and heterocyclyl, wherein the sum of substituents on R1 andR2 together is 0, 1, 2, or 3, and the substituents are independentlychosen from —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆ alkyl), andfluoro; and

R3 is chosen from —H, alkyl, cycloalkyl, haloalkyl, and heterocyclyl,wherein R3 has 0, 1, 2, or 3 substituents independently chosen from—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆ alkyl), and fluoro;

with the proviso that the following compounds are excluded:

-   N1-[(trans)-2-phenylcyclopropyl]-N2-undecyl-rel-1,2-ethanediamine;-   N1-[(trans)-2-phenylcyclopropyl]-N2-tricyclo[3.3.1.13,7]dec-2-yl-rel-1,2-ethanediamine;-   N1-cyclooctyl-N2-[(trans)-2-phenylcyclopropyl]-rel-1,2-ethanediamine;-   N1,N1-dimethyl-N2-(2-phenylcyclopropyl)-1,3-propanediamine;-   N1,N1-dimethyl-N2-(2-phenylcyclopropyl)-1,2-ethanediamine; and-   trans-1-phenyl-2-[(2-hydroxyethyl)amino]cyclopropane.

In a further embodiment, the LSD1 inhibitor or selective LSD1 inhibitoror dual LSD1/MAO-B inhibitor to be used in accordance with the inventionis a 2-cyclylcyclopropan-1-amine compound which is a compound of thefollowing formula (V) or a pharmaceutically acceptable salt or solvatethereof:

(A′)_(X)-(A)-(B)—(Z)-(L)-C(═O)NH₂  (V)

In formula (V), (A) is heteroaryl or aryl;

each (A′), if present, is independently chosen from aryl, arylalkoxy,arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyl, cycloalkyl,haloalkoxy, and cyano, wherein each (A′) is substituted with 0, 1, 2 or3 substituents independently chosen from halo, haloalkyl, aryl,arylalkoxy, alkyl, alkoxy, cyano, sulfonyl, sulfinyl, and carboxamide;

X is 0, 1, 2, or 3;

(B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded todifferent carbon atoms of (B);

(Z) is —NH—; and

(L) is —(CH₂)_(m)CR₁R₂—, wherein m is 0, 1, 2, 3, 4, 5, or 6, andwherein R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

provided that, if (L) is —CH₂— or —CH(CH₃)—, then X is not 0.

In a further embodiment, the LSD1 inhibitor or selective LSD1 inhibitoror dual LSD1/MAO-B inhibitor to be used in accordance with the inventionis a 2-cyclylcyclopropan-1-amine compound which is a compound of thefollowing formula (VI) or an enantiomer, a diastereomer, or a mixturethereof, or a pharmaceutically acceptable salt or solvate thereof:

In formula (VI), E is —N(R3)-, —O—, or —S—, or is —X³═X⁴—;

X¹ and X² are independently C(R2) or N;

X³ and X⁴, when present, are independently C(R2) or N;

(G) is a cyclyl group;

each (R1) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl,-L1-cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl,alkoxy, urea, carbamate, acyl, or carboxyl;

each (R2) is independently chosen from —H, alkyl, alkenyl, alkynyl,cyclyl, -L1-cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl,alkoxy, urea, carbamate, acyl, or carboxyl, wherein each (R2) group has1, 2, or 3 independently chosen optional substituents or two (R2) groupscan be taken together to form a heterocyclyl or aryl group having 1, 2,or 3 independently chosen optional substituents, wherein said optionalsubstituents are independently chosen from alkyl, alkanoyl, heteroalkyl,heterocyclyl, haloalkyl, cycloalkyl, carbocyclyl, arylalkoxy,heterocyclylalkoxy, aryl, aryloxy, heterocyclyloxy, alkoxy, haloalkoxy,oxo, acyloxy, carbonyl, carboxyl, carboxamido, cyano, halogen, hydroxyl,amino, aminoalkyl, amidoalkyl, amido, nitro, thiol, alkylthio, arylthio,sulfonamide, sulfinyl, sulfonyl, urea, or carbamate;

R3 is —H or a (C₁-C₆)alkyl group;

each L1 is independently alkylene or heteroalkylene; and

n is 0, 1, 2, 3, 4 or 5.

In a further embodiment, the LSD1 inhibitor or selective LSD1 inhibitoror dual LSD1/MAO-B inhibitor to be used in accordance with the inventionis a 2-cyclylcyclopropan-1-amine compound which is a compound of thefollowing formula (VII) or an enantiomer, a diastereomer, or a mixturethereof, or a pharmaceutically acceptable salt or solvate thereof:

(A′)_(X)-(A)-(B)—(Z)-(L)-(D)  (VII)

In formula (VII), (A) is heteroaryl or aryl;

each (A′), if present, is independently chosen from aryl, arylalkoxy,arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyl, cycloalkyl,haloalkoxy, and cyano, wherein each (A′) is substituted with 0, 1, 2, or3 substituents independently chosen from halo, haloalkyl, haloalkoxy,aryl, arylalkoxy, alkyl, alkoxy, amido, —CH₂C(═O)NH₂, heteroaryl, cyano,sulfonyl, and sulfinyl;

X is 0, 1, 2, or 3;

(B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded todifferent carbon atoms of (B);

(Z) is —NH—;

(L) is chosen from a single bond, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, and—CH₂CH₂CH₂CH₂—; and

(D) is an aliphatic carbocyclic group or benzocycloalkyl, wherein saidaliphatic carbocyclic group or said benzocycloalkyl has 0, 1, 2, or 3substituents independently chosen from —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)(C₁-C₆ alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, andhaloalkoxy;

with the proviso that the following compounds are excluded:

-   N-(2-phenylcyclopropyl)-cyclopentanamine;-   10,11-dihydro-N-(2-phenylcyclopropyl)-5H-dibenzo[a,d]cyclohepten-5-amine;    and-   trans-N-(2-phenylcyclopropyl)-cyclohexanamine.

In a further embodiment, the LSD1 inhibitor or selective LSD1 inhibitoror dual LSD1/MAO-B inhibitor to be used in accordance with the inventionis a 2-cyclylcyclopropan-1-amine compound which is a compound of thefollowing formula (VIII) or a pharmaceutically acceptable salt orsolvate thereof:

In formula (VIII), E is —X³═X⁴—, —N(R3)-, —S—, or —O—;

X¹ and X² are each independently C(R2) or N:

X³ and X⁴, when present, are each independently C(R2) or N;

L is —NH— or —NH—CH₂—;

G is a cyclyl group;

each R1 is independently chosen from alkyl, alkenyl, alkynyl, cyclyl,-L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl,alkoxy, urea, carbamate, acyl, or carboxyl;

each R2 is independently chosen from —H, alkyl, alkenyl, alkynyl,cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl,alkoxy, urea, carbamate, acyl, or carboxyl, wherein each R2 group has 1,2, or 3 independently chosen optional substituents, and further whereintwo R2 groups bound to adjacent carbon atoms can be taken together toform a heterocyclyl or aryl group having 1, 2, or 3 independently chosenoptional substituents; wherein said optional substituents are eachindependently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl,haloalkyl, cycloalkyl, carbocyclyl, arylalkoxy, heterocyclylalkoxy,aryl, aryloxy, heterocyclyloxy, alkoxy, haloalkoxy, oxo, acyloxy,carbonyl, carboxyl, carboxamido, cyano, halogen, hydroxyl, amino,aminoalkyl, amidoalkyl, amido, nitro, thiol, alkylthio, arylthio,sulfinyl, sulfonyl, sulfonamide, urea or carbamate;

R3 is —H or an (C1-C6)alkyl group;

each L2 is independently chosen from alkylene or heteroalkylene; and

n is 0, 1, 2, 3, 4 or 5.

In a further embodiment, the LSD1 inhibitor or selective LSD1 inhibitoror dual LSD1/MAO-B inhibitor to be used in accordance with the inventionis a 2-cyclylcyclopropan-1-amine compound which is a compound of thefollowing formula (IX) or a pharmaceutically acceptable salt or solvatethereof:

In formula (IX), (A) is a cyclyl group having n substituents (R3);

(B) is a cyclyl group or an -(L1)-cyclyl group, wherein said cyclylgroup or the cyclyl moiety comprised in said -(L1)-cyclyl group has nsubstituents (R2);

(L1) is —O—, —NH—, —N(alkyl)-, alkylene or heteroalkylene;

(D) is a heteroaryl group or an -(L2)-heteroaryl group, wherein saidheteroaryl group or the heteroaryl moiety comprised in said-(L2)-heteroaryl group has one substituent (R1), and further whereinsaid heteroaryl group is covalently bonded to the remainder of themolecule through a ring carbon atom or the heteroaryl moiety comprisedin said -(L2)-heteroaryl group is covalently bonded to the (L2) moietythrough a ring carbon atom;

(L2) is —O—, —NH—, —N(alkyl)-, alkylene or heteroalkylene;

(R1) is a hydrogen bonding group;

each (R2) is independently selected from alkyl, alkenyl, alkynyl,cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy,acyl, carboxyl, carbamate or urea;

each (R3) is independently selected from alkyl, alkenyl, alkynyl,cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy,acyl, carboxyl, carbamate, or urea; and

n is independently 0, 1, 2, 3 or 4.

Exemplary non-limiting selective LSD1 inhibitors are OG Compounds A, B,C and D as shown in FIG. 1 and OG Compounds X and Y shown in Example 2,as well as pharmaceutically acceptable salts or solvates thereof.Exemplary non-limiting dual LSD1/MAO B selective inhibitors are OGCompounds E, F and G as shown in FIG. 2 and OG Compound Z as shown inExample 2, as well as pharmaceutically acceptable salts or solvatesthereof.

The 2-cyclylcyclopropan-1-amine compounds disclosed and describedherein, including, e.g., the compounds of formulae (I) to (IX), can beprepared by methods known in the art of synthetic chemistry. Forexample, these compounds can be prepared in accordance with or inanalogy to the methods described in WO2010/043721, WO2010/084160,WO2011/035941, WO2011/042217, WO2011/131697, PCT/EP2011/062947,PCT/EP2011/062949, and PCT/EP2011/067608.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

As used herein, the term “aryl,” refers a carbocyclic aromatic systemcontaining one ring, or two or three rings fused together where in thering atoms are all carbon. The term “aryl” groups includes, but is notlimited to groups such as phenyl, naphthyl, or anthracenyl.

As used herein, the term “heterocyclyl” or “heterocycle,” each refer toa saturated, partially unsaturated, or fully unsaturated monocyclic,bicyclic, or tricyclic heterocyclic group containing at least oneheteroatom as a ring member, wherein each said heteroatom may beindependently selected from the group consisting of nitrogen, oxygen,and sulfur wherein the nitron or sulfur atoms may be oxidized (e.g.,—N—O, —S(═O)—, or —S(═O)₂—). Additionally, 1, 2, or 3 of the carbonatoms of the heterocyclyl may be optionally oxidized (e.g., to give anoxo group or ═O). One group of heterocyclyls has from 1 to 4 heteroatomsas ring members. Another group of heterocyclyls has from 1 to 2heteroatoms as ring members. One group of heterocyclyls has from 3 to 8ring members in each ring. Yet another group of heterocyclyls has from 3to 7 ring members in each ring. Again another group of heterocyclyls hasfrom 5 to 6 ring members in each ring. “Heterocyclyl” is intended toencompass a heterocyclyl group fused to a carbocyclyl or benzo ringsystems. Examples of heterocyclyl groups include, but are not limitedto, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinylimidazolinyl, or imidazolidinyl. Examplesof heteroaryls that are heterocyclyls include, but are not limited to,pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl,thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, or furopyridinyl.

As used herein, the term “heteroaryl,” refers to a 3 to 7 memberedunsaturated monocyclic ring, or a fused bicyclic, or tricyclic ringsystem in which the rings are aromatic and in which at least one ringcontains at least one atom selected from the group consisting of O, S,and N. One group of heteroaryls has from 5 to 7 ring atoms. Examples ofheteroaryl groups include, but are not limited to, pyridinyl,imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl,thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, or furopyridinyl.

As used herein, the term “acyl,” refers to a carbonyl attached to analkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any othermoiety where the atom attached to the carbonyl is carbon. An “acetyl”group refers to a —C(═O)CH₃ group. An “alkylcarbonyl” or “alkanoyl”group refers to an alkyl group attached to the parent molecular moietythrough a carbonyl group. Examples of such groups include, but are notlimited to, methylcarbonyl or ethylcarbonyl. Examples of acyl groupsinclude, but are not limited to, formyl, alkanoyl or aroyl.

As used herein, the term “alkenyl,” refers to a straight-chain orbranched-chain hydrocarbon group having one or more double bonds andcontaining from 2 to 20 carbon atoms. Exemplary alkenyl groups may havefrom 2 to 6 carbon atoms. A (C2-C6)alkenyl has from 2 to 6 carbon atoms.

As used herein, the term “alkoxy,” refers to an alkyl ether group,wherein the term alkyl is as defined below. Exemplary alkoxy groups mayhave from 1 to 6 carbon atoms. Examples of suitable alkyl ether groupsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or n-pentoxy.

As used herein, the term “alkyl,” refers to a straight-chain orbranched-chain alkyl group containing from 1 to 20 carbon atoms.Exemplary alkyl groups may have from 1 to 10 or, in particular, from 1to 6 carbon atoms. A (C1-C10)alkyl has from 1 to 10 carbon atoms and a(C1-C6)alkyl has from 1 to 6 carbon atoms and a (C1-C4)alkyl has from 1to 4 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neo-pentyl, iso-amyl, hexyl, heptyl,octyl, or nonyl.

As used herein, the term “alkylene” refers to an alkyl group attached attwo positions, i.e. an alkanediyl group. Exemplary alkylene groups mayhave from 1 to 6 carbon atoms. Examples include, but are not limited to,methylene, ethylene, propylene, butylene, pentylene, hexylene,heptylene, octylene, or nonylene.

As used herein, the term “alkylamino,” refers to an alkyl group attachedto the parent molecular moiety through an amino group. Suitablealkylamino groups may be mono- or dialkylated, forming groups including,but not limited to N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-ethylmethylamino, N,N-diethylamino, N-propylamino, andN,N-methylpropylamino.

As used herein, the term “alkynyl,” refers to a straight-chain orbranched-chain hydrocarbon group having one or more triple bonds andcontaining from 2 to 20 carbon atoms. Exemplary alkynyl groups may havefrom 2 to 6 carbon atoms. A (C2-C6)alkynyl has from 2 to 6 carbon atoms.A (C2-C4)alkynyl has from 2 to 4 carbon atoms. Examples of alkynylgroups include, but are not limited to, ethynyl, propynyl,hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl,3-methylbutyn-1-yl, or hexyn-2-yl.

As used herein, the terms “amido” and “carbamoyl,” refer to an aminogroup as described below attached to the parent molecular moiety througha carbonyl group (e.g., —C(═O)NRR′), or vice versa (—N(R)C(═O)NR′).“Amido” and “carbamoyl” encompass “C-amido”, “N-amido” and “acylamino”as defined herein. R and R′ are as defined herein.

As used herein, the term “C-amido,” refers to a —C(═O)NRR′ group with Rand R′ as defined herein.

As used herein, the term “amino,” refers to —NRR′, wherein R and R′ areindependently selected from the group consisting of hydrogen, alkyl,heteroalkyl, aryl, carbocyclyl, and heterocyclyl, Additionally, R and R′may be combined to form a heterocyclyl.

As used herein, the term “arylalkoxy” or “aralkoxy,” refers to an arylgroup attached to the parent molecular moiety through an alkoxy group.Examples of arylalkoxy groups include, but are not limited to, benzyloxyor phenethoxy.

As used herein, the term “arylalkyl” or “aralkyl,” refers to an arylgroup attached to the parent molecular moiety through an alkyl group.

As used herein, the term “aryloxy,” refers to an aryl group attached tothe parent molecular moiety through an oxy (—O—).

As used herein, the term “carbamate,” refers to an O-carbamyl orN-carbamyl group as defined herein.

As used herein, the term “carbonyl,” when alone includes formyl —C(═O)Hand in combination is a —C(═O)— group.

As used herein, the term “carboxyl” or “carboxy” refers to —C(═O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(═O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(═O)OR groups where Ris as defined herein.

As used herein, the term “cyano” refers to —CN.

As used herein, the term “carbocyclyl” refers to a saturated orpartially saturated monocyclic or a fused bicyclic or tricyclic groupwherein the ring atoms of the cyclic system are all carbon and whereineach cyclic moiety contains from 3 to 12 carbon atom ring members.“Carbocyclyl” encompasses benzo fused to a carbocyclyl ring system. Onegroup of carbocyclyls have from 5 to 7 carbon atoms. Examples ofcarbocyclyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, or adamantyl.

As used herein, the term “cycloalkyl” refers to a saturated monocyclic,bicyclic or tricyclic group wherein the ring atoms of the cyclic systemare all carbon and wherein each cyclic moiety contains from 3 to 12carbon atom ring members. One group of cycloalkyls has from 5 to 7carbon atoms. Examples of cycloalkyl groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oradamantyl.

As used herein, the term “cycloalkenyl” refers to a partially saturatedmonocyclic, bicyclic or tricyclic group wherein the ring atoms of thecyclic system are all carbon and wherein each cyclic moiety containsfrom 3 to 12 carbon atom ring members. One group of carboalkenyls havefrom 5 to 7 carbon atoms. Examples of cycloalkenyl groups include, butare not limited to, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

As used herein, the term “cyclyl” refers to an aryl, heterocyclyl, orcarbocyclyl group as defined herein. A “cyclyl” group may, for example,be an aryl group, a cycloalkyl group, a heteroaryl group or aheterocycloalkyl group.

As used herein, the term “halo” or “halogen” refers to fluorine,chlorine, bromine, or iodine.

As used herein, the term “haloalkoxy” refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom. Examplesof haloalkoxy groups include, but are not limited to, trifluoromethoxy,2-fluoroethoxy, or 3-chloropropoxy.

As used herein, the term “haloalkyl” refers to an alkyl group having themeaning as defined above wherein one or more hydrogens are replaced witha halogen. Specifically embraced are monohaloalkyl, dihaloalkyl orpolyhaloalkyl groups. A monohaloalkyl group, for one example, may havean iodo, bromo, chloro or fluoro atom within the group. Dihalo orpolyhaloalkyl groups may have two or more of the same halo atoms or acombination of different halo groups. Examples of haloalkyl groupsinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl ordichloropropyl.

As used herein, the term “heteroalkyl” refers to a straight or branchedalkyl chain, as defined herein above (e.g., an alkyl chain having from 1to 6 carbon atoms), wherein one, two, or three carbons forming the alkylchain are each replaced by a heteroatom independently selected from thegroup consisting of O, N, and S, and wherein the nitrogen and/or sulfurheteroatom(s) (if present) may optionally be oxidized and the nitrogenheteroatom(s) (if present) may optionally be quaternized. Theheteroatom(s) O, N and S may, for example, be placed at an interiorposition of the heteroalkyl group, i.e., the heteroalkyl may be bound tothe remainder of the molecule via a carbon atom. Up to two heteroatomsmay be consecutive, such as, for example, —CH₂—NH—OCH₃.

As used herein, the term “heteroalkylene” refers to a heteroalkyl groupattached at two positions. Examples include, but are not limited to,—CH₂OCH₂—, —CH₂SCH₂—, and —CH₂NHCH₂—, —CH₂S—, or —CH₂NHCH(CH₃)CH₂—.

As used herein, the term “heterocycloalkyl,” refers to a heterocyclylgroup that is not fully unsaturated e.g., one or more of the ringssystems of a heterocycloalkyl is not aromatic. Examples ofheterocycloalkyls include piperazinyl, morpholinyl, piperidinyl, orpyrrolidinyl.

As used herein, the term “hydroxyl,” as used herein, refers to —OH.

As used herein, the term “hydroxyalkyl,” as used herein, refers to ahydroxyl group attached to the parent molecular moiety through an alkylgroup.

As used herein, the phrase “in the main chain,” refers to the longestcontiguous or adjacent chain of carbon atoms starting at the point ofattachment of a group to the compounds of any one of the formulasdisclosed herein.

As used herein, the term phrase “linear chain of atoms” refers to thelongest straight chain of atoms independently selected from carbon,nitrogen, oxygen and sulfur.

As used herein, the term “lower,” where not otherwise specificallydefined, means containing from 1 to and including 6 carbon atoms.

As used herein, the term “lower aryl,” means phenyl or naphthyl.

As used herein, the term “lower heteroaryl,” means either 1) monocyclicheteroaryl comprising five or six ring members, of which between one andfour said members may be heteroatoms selected from O, S, or N.

As used herein, the terms “benzo” and “benz,” refer to the divalentgroup C₆H₄=derived from benzene. Examples include, but are not limitedto, benzothiophene or benzimidazole.

As used herein, the term “nitro,” refers to —NO₂.

As used herein, the terms “sulfonate” “sulfonic acid” and “sulfonic,”refers to the —SO₃H group and its anion as the sulfonic acid is used insalt formation.

As used herein, the term “sulfanyl,” to —S—.

As used herein, the term “sulfinyl,” refers to —S(═O)(R)—, with R asdefined herein.

As used herein, the term “sulfonyl,” refers to —S(═O)₂R, with R asdefined herein.

As used herein, the term “sulfonamide” or “sulfonamido”, refers to anN-sulfonamido or S-sulfonamido group as defined herein. As used herein,the term “N-sulfonamido,” refers to a RS(═O)₂N(R′)— group with R and R′as defined herein. Exemplary, non-limiting N-sulfonamido groups are—NHSO₂alkyl such as —NHSO₂CH₃, —NHSO₂CH₂CH₃ or —NHSO₂(isopropyl), and—NHSO₂ (optionally substituted aryl) such as —NHSO₂phenyl. As usedherein, the term “S-sulfonamido,” refers to a —S(═O)₂NRR′, group, with Rand R′ as defined herein.

As used herein, the term “urea,” refers to a —N(R)C(═O)N(R) groupwherein R and R′ are as defined herein.

As used herein, “hydrogen bonding group” refers to a substituent group,which is capable of taking part in a non-covalent bonding betweenhydrogen and another atom (usually nitrogen or oxygen). Examplesinclude, but are not limited to, —OH, NH₂, —OH, amido, —S(O)₂NH₂,—C(═O)NH₂, —CH₂—C(═O)NH₂, and —CH₂—NH₂.

As used herein, the term “optionally substituted” means the preceding oranteceding group may be substituted or unsubstituted. When substituted,the substituents of an “optionally substituted” group may include,without limitation, one or more substituents independently selected fromthe following groups or a particular designated set of groups, alone orin combination: lower alkyl, lower alkenyl, lower alkynyl, loweralkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl,lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy,oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lowercarboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxyl,amino, lower alkylamino, arylamino, aminoalkyl, amido, nitro, thiol,lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio,sulfonate, sulfonic acid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃,CO₂CH₃, CO₂H, pyridinyl, thiophene, furanyl, carbamate, and urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.” In one specific definition, the optionalsubstituents are chosen from hydroxyl, halo, alkyl, alkoxy, haloalkyl,haloalkoxy, —N((C1-C3)alkyl)₂, —NH((C1-C3)alkyl),—NHC(═O)((C1-C3)alkyl), —C(═O)OH, —C(═O)O((C1-C3)alkyl),—C(═O)(C1-C3)alkyl), —C(═O)NH₂, —C(═O)NH(C1-C3)alkyl),—C(═O)NH(cycloalkyl), —C(═O)N(C1-C3)alkyl)₂, —S(═O)₂((C1-C3)alkyl),—S(═O)₂NH₂, —S(═O)₂N((C1-C3)alkyl)₂, —S(═O)₂NH((C1-C3)alkyl), —CHF₂,—OCF₃, —OCHF₂, —SCF₃, —CF₃, —CN, —NH₂, —NO₂, or tetrazolyl.

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl,heteroaryl and heterocycloalkyl. Whether an R group has a numberdesignation or not, every R group, including R, R′ and R^(p) where p=(1,2, 3, . . . p), every substituent, and every term should be understoodto be independent of every other in terms of selection from a group.Should any variable, substituent, or term (e.g., aryl, heterocycle, R,etc.) occur more than one time in a formula or generic structure, itsdefinition at each occurrence is independent of the definition at everyother occurrence. Those of skill in the art will further recognize thatcertain groups may be attached to a parent molecule or may occupy aposition in a chain of elements from either end as written. Thus, by wayof example only, an unsymmetrical group such as —C(═O)N(R)— may beattached to the parent moiety at either the carbon or the nitrogen.

As used herein, the term “2-cyclylcyclopropan-1-amine compound” refersto a compound comprising a 2-cyclylcyclopropan-1-amine moiety or apharmaceutically acceptable salt or solvate thereof. Exemplary2-cyclylcyclopropan-1-amine compounds are, without limitation,2-arylcyclopropan-1-amine compounds (such as 2-phenylcyclopropan-1-aminecompounds) and 2-heteroarylcyclopropan-1-amine compounds (such as2-pyridinylcyclopropan-1-amine compounds or2-thiazolylcyclopropan-1-amine compounds).

As used herein, the term “2-arylcyclopropan-1-amine compound” refers toa compound comprising a 2-arylcyclopropan-1-amine moiety or apharmaceutically acceptable salt or solvate thereof.

As used herein, the term “2-heteroarylcyclopropan-1-amine compound”refers to a compound comprising a 2-heteroarylcyclopropan-1-amine moietyor a pharmaceutically acceptable salt or solvate thereof.

As used herein, the term “2-phenylcyclopropan-1-amine compound” refersto a compound comprising a 2-phenylcyclopropan-1-amine moiety or apharmaceutically acceptable salt or solvate thereof.

As used herein, the term “2-pyridinylcyclopropan-1-amine compound”refers to a compound comprising a 2-pyridinylcyclopropan-1-amine moietyor a pharmaceutically acceptable salt or solvate thereof.

As used herein, the term “2-thiazolylcyclopropan-1-amine compound”refers to a compound comprising a 2-thiazolylcyclopropan-1-amine moietyor a pharmaceutically acceptable salt or solvate thereof.

As used herein, the term “phenelzine compound” refers to a compoundcomprising a 2-phenylethylhydrazine moiety or a pharmaceuticallyacceptable salt or solvate thereof.

As used herein, the term “propargylamine compound” refers to a compoundcomprising a propargylamine moiety or a pharmaceutically acceptable saltor solvate thereof. An exemplary propargylamine compound is, withoutlimitation, pargyline (N-benzyl-N-methylprop-2-yn-1-amine).

In reference to the substituents referred to above, as the skilledartisan is aware, the appropriate selection of the substituents can bemade in view of the disclosure herein to provide LSD1 inhibitors,selective LSD1 inhibitors, and dual LSD1/MAOB inhibitors for use in themethods and compositions of the invention.

Other LSD1 inhibitors include, but are not limited to those e.g.,disclosed in Ueda et al. ((2009) J. Am. Chem Soc. 131(48):17536-17537)including; Binda et al. (J Am Chem Soc. 2010 May 19; 132(19):6827-33).Mimasu et al. ((2010) Biochemistry June 22. [Epub ahead of print]PMID:20568732 [PubMed—as supplied by publisher].

Other phenylcyclopropylamine derivatives and analogs are found e.g., inKaiser et al. ((1962) J. Med. Chem. 5:1243-1265); Zirkle et al. ((1962)J. Med. Chem. 1265-1284; U.S. Pat. Nos. 3,365,458; 3,471,522; 3,532,749)and Bolesov et al. ((1974) Zhurnal Organicheskoi Khimii 10:8 1661-1669)and Russian Patent No. 230169 (19681030).

Preferably, the LSD1 inhibitor for use in the invention is a selectiveLSD1 inhibitor or dual inhibitor of LSD1 and MAOB. In one preferredaspect, the selective LSD1 or dual LSD1 MAOB inhibitor has a molecularweight of less than 700. In one preferred aspect, the selective LSD1 ordual LSD1 MAOB inhibitor has a molecular weight of less than 500. In onepreferred aspect, the selective LSD1 or dual LSD1 MAOB inhibitor has amolecular weight of less than 300.

Preferably, the LSD1 inhibitor comprises five or less amide bonds(—NH—C═O). Preferably, the LSD1 inhibitor comprises three or less amidebonds (—NH—C═O).

In one aspect, the LSD1 inhibitor for use in the invention has zeroamide bonds.

In one aspect, the selective LSD1 and dual LSD1/MAOB inhibitors for usein the invention desirably inhibits LSD1 and/or MAOB selectivelycompared to MAOA, thus avoiding deleterious side effects associated withadministration to animals, including humans, of MAOA inhibitors. As theinventors have described herein, the selective LSD1 inhibitors and thedual LSD1/MAOB inhibitors can be administered in a such a way to anindividual e.g., a mammal or human, to achieve concentration in vivothat are expected to inhibit LSD1 and/or MAO-B while avoiding thetoxicity associated with inhibition of MAOA and these concentrations aresufficient enough to improve specific phenotypes or symptoms associatedwith Flaviviridae infection or HCV infection.

In another aspect, the selective LSD1 and dual LSD11/MAOB inhibitors foruse in the invention desirably inhibit LSD1 and/or MAOB targeting a hostcell protein involved in Flaviviridae infection. Without wishing to bebound by theory targeting Flaviviridae with LSD1 inhibitors can avoid orlessen the ability of the virus to develop resistance to therapy aloneor in combination with an interferon agent or an agent targeting a viralprotein such as a protease inhibitor or a nucleoside or non-nucleosidepolymerase inhibitor or an NS5A inhibitor. As the inventors havedescribed herein, the selective LSD1 inhibitors and the dual LSD1/MAOBinhibitors can be administered in a such a way to an individual e.g., amammal or human, to achieve concentration in vivo that are expected toinhibit LSD1 and/or MAO-B while avoiding the toxicity associated withinhibition of MAOA and these concentrations are sufficient enough toimprove specific phenotypes or symptoms associated with Flaviviridae orHCV infection.

In one aspect, the selective LSD1 and dual LSD1/MAOB inhibitors for usein the invention desirably inhibit LSD1 and/or MAOB targeting a hostcell protein involved in Flaviviridae infection. Without wishing to bebound by theory targeting Flaviviridae with LSD1 inhibitors can avoid orlessen the side effects associated with treatment with interferon agentor an agent targeting a viral protein such as a protease inhibitor or anucleoside or non-nucleoside polymerase inhibitor or an NS5A inhibitor.As the inventors have described herein, the selective LSD1 inhibitorsand the dual LSD1/MAOB inhibitors can be administered in a such a way toan individual e.g., a mammal or human, to achieve concentration in vivothat are expected to inhibit LSD1 and/or MAO-B while avoiding thetoxicity associated with inhibition of MAOA and these concentrations aresufficient enough to improve specific phenotypes or symptoms associatedwith Flaviviridae or HCV infection.

In still another aspect, the selective LSD1 and dual LSD1/MAOBinhibitors for use in the invention desirably inhibit LSD1 and/or MAOBtargeting a host cell protein involved in HCV infection. Without wishingto be bound by theory targeting HCV with LSD1 inhibitors can avoid orlessen the side effects associated with treatment with interferon agentor an agent targeting a viral protein such as a protease inhibitor or anucleoside or non-nucleoside polymerase inhibitor or an NS5A inhibitor.As the inventors have described herein, the selective LSD1 inhibitorsand the dual LSD1/MAOB inhibitors can be administered in a such a way toan individual e.g., a mammal or human, to achieve concentration in vivothat are expected to inhibit LSD1 and/or MAO-B while avoiding thetoxicity associated with inhibition of MAOA and these concentrations aresufficient enough to improve specific phenotypes or symptoms associatedwith HCV infection.

The invention provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound which is a selectiveinhibitor of LSD1. Preferably, LSD1 selective inhibitors have IC50values for LSD1 which are at least 2-fold lower than the IC50 value forMAOA and/or MAOB. Even more preferably, LSD1 selective inhibitors haveIC50 values for LSD1 which are at least 5-fold lower than the IC50 valuefor MAOA and/or MAOB. Yet even more preferably, LSD1 selectiveinhibitors have IC50 values for LSD1 which are at least 10-fold lowerthan the IC50 value for MAOA and/or MAOB. The ability of a compound toinhibit LSD1 and its IC50 values for LSD1, MAO-A and MAO-B can bedetermined in accordance with the experimental protocol described inExample 1. In one specific embodiment, dual selective LSD1/selectiveinhibitor for use in the invention are as defined above and is chosenfrom a phenylcyclopropylamine derivative or analog, a phenelzinederivative or analog, or a propargylamine derivative or analog. Inanother embodiment, the selective LSD1 inhibitor for use in theinvention is chosen from a 2-cyclylcyclopropan-1-amine compound, aphenelzine compound and a propargylamine compound; more preferably, theLSD1 inhibitor for use in the invention is a 2-cyclylcyclopropan-1-aminecompound, preferably a 2-arylcyclopropan-1-amine compound or a2-heteroarylcyclopropan-1-amine compound, and still more preferably a2-phenylcyclopropan-1-amine compound, 2-pyridinylcyclopropan-1-aminecompound or a 2-thiazolylcyclopropan-1-amine compound.

The invention also provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound which is a dualinhibitor selective for LSD1 and MAOB. Preferably, dual LSD1/MAOBselective inhibitors have IC50 values for LSD1 and MAOB which are atleast 2-fold lower than the IC50 value for MAO-A. Even more preferably,dual LSD1/MAOB selective inhibitors have IC50 values for LSD1 and MAOBwhich are at least 5-fold lower than the IC50 value for MAO-A. Yet evenmore preferably, dual LSD1/MAOB selective inhibitors have C150 valuesfor LSD1 and MAOB which are at least 10-fold lower than the IC50 valuefor MAO-A. The ability of a compound to inhibit LSD1 and MAO-B and itsIC50 values for LSD1, MAO-A and MAO-B can be determined in accordancewith the experimental protocol described in Example 1 In one specificembodiment, dual selective LSD1/selective inhibitors for use in theinvention are as defined above and are chosen from aphenylcyclopropylamine derivative or analog, a phenelzine derivative oranalog, or a propargylamine derivative or analog. In another embodiment,the dual LSD1/MAOB inhibitor for use in the invention is chosen from a2-cyclylcyclopropan-1-amine compound, a phenelzine compound and apropargylamine compound; more preferably, the dual LSD1/MAOB inhibitorfor use in the invention is a 2-cyclylcyclopropan-1-amine compound,preferably a 2-arylcyclopropan-1-amine compound or a2-heteroarylcyclopropan-1-amine compound, and still more preferably a2-phenylcyclopropan-1-amine compound, 2-pyridinylcyclopropan-1-aminecompound or a 2-thiazolylcyclopropan-1-amine compound.

Typically, compounds for use as selective LSD1 inhibitors or dualinhibitors of LSD1 and MAOB can be effective in an amount of from about0.01 μg/kg to about 100 mg/kg per day based on total body weight. Theactive ingredient may be administered at once, or may be divided into anumber of smaller doses to be administered at predetermined intervals oftime. The suitable dosage unit for humans for each administration canbe, e.g., from about 1 μg to about 2000 mg, preferably from about 5 μgto about 1000 mg, and even more preferably from about 0.5 mg to about500 mg. The active ingredient can be administered orally or by otherroutes of administration e.g., IP, IV, etc. Preferably, the inhibitor isformulated and delivered in such a way as to achieve concentration invivo that modulate the target activity e.g., LSD1 and/or MAOB. Thus, ina specific embodiment, the effective amount of compound ranges from 0.05μg/kg to about 100 mg/kg per day based on total body weight, preferablyfrom 0.05 μg/kg to about 50 mg/kg.

It should be understood that the dosage ranges set forth above areexemplary only and are not intended to limit the scope of this inventionunless specified. The therapeutically effective amount for each activecompound can vary with factors including but not limited to the activityof the compound used, stability of the active compound in the patient'sbody, the severity of the conditions to be alleviated, the total weightof the patient treated, the route of administration, the ease ofabsorption, distribution, and excretion of the active compound by thebody, the age and sensitivity of the patient to be treated, and thelike, as will be apparent to a skilled artisan. The amount ofadministration can be adjusted as the various factors change over time.

For oral delivery, the active compounds can be incorporated into aformulation that includes pharmaceutically acceptable carriers such asbinders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g.,starch, lactose), lubricants (e.g., magnesium stearate, silicondioxide), disintegrating agents (e.g., alginate, Primogel, and cornstarch), and sweetening or flavoring agents (e.g., glucose, sucrose,saccharin, methyl salicylate, and peppermint). The formulation can beorally delivered in the form of enclosed gelatin capsules or compressedtablets. Capsules and tablets can be prepared in any conventionaltechniques. The capsules and tablets can also be coated with variouscoatings known in the art to modify the flavors, tastes, colors, andshapes of the capsules and tablets. In addition, liquid carriers such asfatty oil can also be included in capsules.

Suitable oral formulations can also be in the form of suspension, syrup,chewing gum, wafer, elixir, and the like. If desired, conventionalagents for modifying flavors, tastes, colors, and shapes of the specialforms can also be included. In addition, for convenient administrationby enteral feeding tube in patients unable to swallow, the activecompounds can be dissolved in an acceptable lipophilic vegetable oilvehicle such as olive oil, corn oil and safflower oil.

The active compounds can also be administered parenterally in the formof solution or suspension, or in lyophilized form capable of conversioninto a solution or suspension form before use. In such formulations,diluents or pharmaceutically acceptable carriers such as sterile waterand physiological saline buffer can be used. Other conventionalsolvents, pH buffers, stabilizers, anti-bacteria agents, surfactants,and antioxidants can all be included. For example, useful componentsinclude sodium chloride, acetates, citrates or phosphates buffers,glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol,propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, andthe like. The parenteral formulations can be stored in any conventionalcontainers such as vials and ampoules.

Routes of topical administration include nasal, bucal, mucosal, rectal,or vaginal applications. For topical administration, the activecompounds can be formulated into lotions, creams, ointments, gels,powders, pastes, sprays, suspensions, drops and aerosols. Thus, one ormore thickening agents, humectants, and stabilizing agents can beincluded in the formulations. Examples of such agents include, but arenot limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum,beeswax, or mineral oil, lanolin, squalene, and the like. A special formof topical administration is delivery by a transdermal patch. Methodsfor preparing transdermal patches are disclosed, e.g., in Brown, et al.(1988) Ann. Rev. Med. 39:221-229 which is incorporated herein byreference.

Subcutaneous implantation for sustained release of the active compoundsmay also be a suitable route of administration. This entails surgicalprocedures for implanting an active compound in any suitable formulationinto a subcutaneous space, e.g., beneath the anterior abdominal wall.See, e.g., Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogelscan be used as a carrier for the sustained release of the activecompounds. Hydrogels are generally known in the art. They are typicallymade by crosslinking high molecular weight biocompatible polymers into anetwork, which swells in water to form a gel like material. Preferably,hydrogels are biodegradable or biosorbable. For purposes of thisinvention, hydrogels made of polyethylene glycols, collagen, orpoly(glycolic-co-L-lactic acid) may be useful. See, e.g., Phillips etal. (1984) J. Pharmaceut. Sci., 73: 1718-1720.

The active compounds can also be conjugated, to a water solublenon-immunogenic non-peptidic high molecular weight polymer to form apolymer conjugate. For example, an active compound is covalently linkedto polyethylene glycol to form a conjugate. Typically, such a conjugateexhibits improved solubility, stability, and reduced toxicity andimmunogenicity. Thus, when administered to a patient, the activecompound in the conjugate can have a longer half-life in the body, andexhibit better efficacy. See generally, Burnham (1994) Am. J. Hosp.Pharm. 15:210-218. PEGylated proteins are currently being used inprotein replacement therapies and for other therapeutic uses.

For example, PEGylated interferon (PEG-INTRON A®) is clinically used fortreating Hepatitis B. PEGylated adenosine deaminase (ADAGEN®) is beingused to treat severe combined immunodeficiency disease (SCIDS).PEGylated L-asparaginase (ONCAPSPAR®) is being used to treat acutelymphoblastic leukemia (ALL). It is preferred that the covalent linkagebetween the polymer and the active compound and/or the polymer itself ishydrolytically degradable under physiological conditions. Suchconjugates known as “prodrugs” can readily release the active compoundinside the body. Controlled release of an active compound can also beachieved by incorporating the active ingredient into microcapsules,nanocapsules, or hydrogels generally known in the art. Otherpharmaceutically acceptable prodrugs of the compounds of this inventioninclude, but are not limited to, esters, carbonates, thiocarbonates,N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivativesof tertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates,phosphate esters, metal salts and sulfonate esters.

Liposomes can also be used as carriers for the active compounds of thepresent invention. Liposomes are micelles made of various lipids such ascholesterol, phospholipids, fatty acids, and derivatives thereof.Various modified lipids can also be used. Liposomes can reduce thetoxicity of the active compounds, and increase their stability. Methodsfor preparing liposomal suspensions containing active ingredientstherein are generally known in the art. See, e.g., U.S. Pat. No.4,522,811; Prescott, Ed., Methods in Cell Biology, Volume XIV, AcademicPress, New York, N.Y. (1976).

The active ingredient can be formulated as a pharmaceutically acceptablesalt. A “pharmaceutically acceptable salt” is intended to mean a saltthat retains the biological effectiveness of the free acids and bases ofthe specified compound and that is not biologically or otherwiseundesirable. A compound for use in the invention may possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of inorganic or organicbases, and inorganic and organic acids, to form a pharmaceuticallyacceptable salt. Exemplary pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the presentinvention with a mineral or organic acid or an inorganic base, such assalts including sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrophosphates, dihydrophosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4 dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates,glycollates, tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, or mandelates.

As used herein, a “pharmaceutically acceptable carrier” refers to anon-API (API refers to Active Pharmaceutical Ingredient) substances suchas disintegrators, binders, fillers, and lubricants used in formulatingpharmaceutical products. They are generally safe for administering tohumans according to established governmental standards, including thosepromulgated by the United States Food and Drug Administration and theEuropean Medical Agency.

The active compounds can also be administered in combination withanother active agent that synergistically treats or prevents the samesymptoms or is effective for another disease or symptom in the patienttreated so long as the other active agent does not interfere with oradversely affect the effects of the active compounds of this invention.Such other active agents include but are not limited toanti-inflammation agents, antiviral agents, antibiotics, antifungalagents, antithrombotic agents, cardiovascular drugs, cholesterollowering agents, anti-cancer drugs, hypertension drugs, and the like.

As used herein the term “hepatitis C” or “HCV” refers to any of thestrains and isolates of hepatitis C that have been identified or areidentifiable according to known classifications and methods. The term“hepatitis C” or “HCV” is intended to encompass all currently knownstrains, types and subtypes of HCV as wells those discovered andclassified as HCV in the future. The identification of HCV is wellwithin the purvey of an ordinary skilled artisan. The first known HCVisolate was identified in the USA (see Q.-L. Choo et al. (1989) Science244: 359-362, Q.-L. Choo et al. (1990) Brit. Med. Bull. 46: 423-441,Q.-L. Choo et al., Proc. Natl. Acad. Sci. 88: 2451-2455 (1991). NumerousHCV strains, types, and subtypes are known with their sequences beingdeposited in public databases. Examples include, but are not limited to,GenBank accession numbers AF177036, AF169002, D28917, AF169003, D84262,AF238484, Y12083, AB047639, AB047641, D63821, and the such.

As used herein, the term “interferon agent” or “alpha interferon” or“interferon alpha” or “a-interferon” refers to the family of interferonproteins that inhibit viral replication, inhibit cellular proliferation,and modulate immune response. The term “alpha interferon” encompasses avariety of commercially available alpha interferons, including, but notlimited to, Roferon A interferon (Hoffman-La Roche, Nutley, N.J.),Berofor alpha 2 (Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield,Conn.), Sumiferon (Sumitomo, Japan), Wellferon interferon alpha-n1(Glaxo-Wellcome Ltd., London, Great Britain). Alpha interferon 2bcurrently has the broadest approval throughout the world for use intreating HCV. U.S. Pat. No. 4,530,901 (which is hereby incorporated byreference in its entirety) provides a description of the manufacture ofalpha interferon 2b.

As used herein, the term “diagnosed with HCV” refers to an individual inwhich a HCV marker has been detected. A variety of HCV markers are knownin the art and can be readily measured by a skilled artisan. Forexample, HCV can be detected by testing for antibodies against HCV(anti-HCV) in a patient or suspected carrier's blood serum.

Another approach to detecting HCV is to test for HCV RNA in the serum ofa patient or suspected carrier using a PCR based assay. Recombinantimmunoblots can also be used to detect HCV. In this test serum isincubated with four recombinant viral proteins that are blotted onnitrocellulose strips. A simple color change indicates antibodies arepresent in the serum that bind to the viral proteins. Furthermore, newmethods for detecting HCV are continually being developed and themethods can be employed for diagnosing HCV infection.

As used herein, the term “side effects of alpha interferon treatment”include fatigue, muscle aches, headaches, nausea, vomiting, low-gradefever, weight loss, irritability, depression, mild bone marrowsuppression, and hair loss.

As used herein, the term “side effects associated with ribavirintreatment” refers to anemia, fatigue and irritability, itching, skinrash, nasal congestion, sinusitis, and cough associated with theadministration of ribavirin to an individual.

As used herein, the term “alleviate a symptom associated with HCV”refers to a lessening of fatigue, dark urine, abdominal pain, nausea,tenderness in the upper right quadrant, poor appetite, muscle and jointpain, cirrhosis (with symptoms such as enlarged liver, enlarged spleen,jaundice, muscle wasting excoriations, ascites and ankle swelling).

The term also encompasses symptoms not associated with the liver,including, but not limited to, cryoglobulinemia symptoms such as skinrashes, joint and muscle aches, kidney disease, neuropathy,cryoglobulins, rheumatoid factor, low complement levels in serum,glomerulonephritis, or porphyria cutanca tarda. The term is also meantto encompass the alleviation of symptoms associated with disease thatare thought to be or might be associated with chronic HCV includingseronegative arthritis, keratoconjunctivitis sicca (Sjogren's syndrome),non-Hodgkin's type B-cell lymphomas, fibromyalgia, or lichen planus.

As used herein, the term “individual in need of treatment” encompassesindividuals who have symptoms of Flaviviridae infection, such as HCVinfection, those who have been diagnosed with Flaviviridae infection ordisease caused by Flaviviridae, such as those diagnosed with HCV, orthose in need of prophylaxis. An “individual in need of treatment” canhave anti-HCV, HCV RNA, elevated serum aminotransferase levels, and/orevidence of chronic hepatitis.

As used herein, the term “ribavirin” refers to1-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide.

As used herein, the term “reversible amine oxidase” inhibitor refers tothe class of compounds that inhibit MAOA or MAOB in a reversible mannerthat are well known in the art. Reversible amine oxidase inhibitors canbe designed to increase selectivity for LSD1 using medicinal chemistryapproaches.

As used herein, the term “irreversible amine oxidase” inhibitor refersto the class of compounds that inhibit MAOA or MAOB in an irreversiblemanner that are well known in the art. Examples of irreversible MAOinhibitors include phenylcyclopropylamine, phenelzine, and pargyline.Irreversible amine oxidase inhibitors can be designed to increaseselectivity for LSD1 using medicinal chemistry approaches.

In reference to the other anti-HCV agents referred to herein, terms suchas VX950, R7227, Telaprevir are intended to encompass the active agentas well as any salt forms of the active agent, and the particular saltform of the active agent that is in development or marketed unlessotherwise specified.

There examples described herein are intended to illustrate differentaspects of the invention by exemplification and are not intended tolimit the scope of the claims or invention.

EXAMPLES Example 1 Biochemical Assays

Compounds for use in the methods of the invention can be identified bytheir ability to inhibit LSD1. The ability of the compounds of theinvention to inhibit LSD1 can be tested as follows. Human recombinantLSD1 protein was purchased from BPS Bioscience Inc. In order to monitorLSD1 enzymatic activity and/or its inhibition rate by our inhibitor(s)of interest, di-methylated H3-K4 peptide (Millipore) was chosen as asubstrate. The demethylase activity was estimated, under aerobicconditions, by measuring the release of H₂O₂ produced during thecatalytic process, using the Amplex® Red peroxide/peroxidase-coupledassay kit (Invitrogen).

Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, inthe absence and/or in the presence of various concentrations ofinhibitor (e.g., from 0 to 75 μM, depending on the inhibitor strength).Tranylcypromine (Biomol International) was used as a control forinhibition. Within the experiment, each concentration of inhibitor wastested in triplicate. After leaving the enzyme interacting with theinhibitor, 12.5 μM of di-methylated H3-K4 peptide was added to eachreaction and the experiment was left for 1 hour at 37° C. in the dark.The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4buffer. At the end of the incubation, Amplex® Red reagent andhorseradish peroxidase (HPR) solution were added to the reactionaccording to the recommendations provided by the supplier (Invitrogen),and left to incubate for 30 extra minutes at room temperature in thedark. A 1 μM H₂O₂ solution was used as a control of the kit efficiency.The conversion of the Amplex® Red reagent to resorufin due to thepresence of H₂O₂ in the assay, was monitored by fluorescence (excitationat 540 nm, emission at 590 nm) using a microplate reader (Infinite 200,Tecan). Arbitrary units were used to measure level of H₂O₂ produced inthe absence and/or in the presence of inhibitor.

The maximum demethylase activity of LSD1 was obtained in the absence ofinhibitor and corrected for background fluorescence in the absence ofLSD1. The Ki (IC50) of each inhibitor was estimated at half of themaximum activity.

Human recombinant monoamine oxidase proteins MAO-A and MAO-B werepurchased from Sigma Aldrich. MAOs catalyze the oxidative deamination ofprimary, secondary and tertiary amines. In order to monitor MAOenzymatic activities and/or their inhibition rate by inhibitor(s) ofinterest, a fluorescent-based (inhibitor)-screening assay was set up.3-(2-Aminophenyl)-3-oxopropanamine (kynuramine dihydrobromide, SigmaAldrich), a non fluorescent compound was chosen as a substrate.Kynuramine is a non-specific substrate for both MAOs activities. Whileundergoing oxidative deamination by MAO activities, kynuramine isconverted into 4-hydroxyquinoline (4-HQ), a resulting fluorescentproduct.

The monoamine oxidase activity was estimated by measuring the conversionof kynuramine into 4-hydroxyquinoline. Assays were conducted in 96-wellblack plates with clear bottom (Corning) in a final Volume of 100 μL.The assay buffer was 100 mM HEPES, pH 7.5. Each experiment was performedin triplicate within the same experiment.

Briefly, a fixed amount of MAO (0.25 μg for MAO-A and 0.5 μg for MAO-B)was incubated on ice for 15 minutes in the reaction buffer, in theabsence and/or in the presence of various concentrations of inhibitor(e.g., from 0 to 50 μM, depending on the inhibitor strength).Tranylcypromine (Biomol International) was used as a control forinhibition.

After leaving the enzyme(s) interacting with the inhibitor, 60 to 90 μMof kynuramine was added to each reaction for MAO-B and MAO-A assayrespectively, and the reaction was left for 1 hour at 37° C. in thedark. The oxidative deamination of the substrate was stopped by adding50 μL (v/v) of NaOH 2N. The conversion of kynuramine to4-hydroxyquinoline, was monitored by fluorescence (excitation at 320 nm,emission at 360 nm) using a microplate reader (Infinite 200, Tecan).Arbitrary units were used to measure levels of fluorescence produced inthe absence and/or in the presence of inhibitor.

The maximum of oxidative deamination activity was obtained by measuringthe amount of 4-hydroxyquinoline formed from kynuramine deamination inthe absence of inhibitor and corrected for background fluorescence inthe absence of MAO enzymes. The Ki (IC50) of each inhibitor wasdetermined at Vmax/2.

Example 2 LSD1 and LSD1/MAOB Dual Inhibitors

Compound LSD1 IC50 MAOA IC50 MAO B IC50 No. (uM) (uM) (uM) Dual-1<0.20 >1.0 <0.20 Dual-2 <0.20 >40 <0.30 Selective-1 <0.10 >1.0 >1.0Selective-2 <0.10 >1.0 >1.0 uM = μM

Other specific examples of LSD1 inhibitors include Compound X

Compound Y

which are both selective LSD1 inhibitors

and Compound Z

which is a dual LSD1/MAOB inhibitor.

Example 3 LSD1 and LSD1/MAO-B Dual Inhibitors Increase Histone LysineMethylation in Cell Based Assays

Histone from SH-SY5Y cells grown in the presence of Compound Dual-1 (adual LSD1/MAOB inhibitor) or tranylcypromine (parnate) for 1, 2, and 3days were extracted and subjected to western blot analysis using acommercially available antibody specific for dimethylated H—K4. B-actinwas used as a loading control.

The results of a western blot stained for H3K4 methylation with SH-SY5Ycells grown in the presence of Compound Dual-1 or tranylcypromine(parnate) for 1, 2, and 3 days, show that this compound, Dual-1,increases H3K4 methylation in cells in a time dependent manner andfurthermore Compound Dual-1 appears to be 10-fold or more potent atincreasing global dimethylated H3K4 levels as compared totranylcypromine.

Furthermore, the inventors have conducted similar studies for other dualinhibitors of LSD1/MAOB and with selective LSD1 inhibitors and foundthat these compounds can increase dimethylated H3K4 levels in similarlyperformed assays.

Example 4 LSD1 Inhibitors can be Administered Safely to Mammals

Maximum tolerated dose studies and pharmacokinetics for several LSD1inhibitors were assessed to determine if the compounds can beadministered to mammals safely at doses that are expected to achievetherapeutic effects. In particular, Compound X was given to mice IP at20 mg/kg, 40 mg/kg and 60 mg/kg daily for 5 days in a MTD studyconducted at Leitat. The results of these studies showed that thesedoses were tolerated with acceptable toxicity. Furthermore, PK studiesshowed that such doses achieved Cmax values that are expected to resultin therapeutic levels of LSD1 inhibitor in mammals.

Example 5 LSD1 Inhibitors Inhibit HCV RNA Replication

Anti-HCV assays were conducted at Southern Research Organization usingan HCV RNA replicon with a luciferase reporter.

Southern Research reports that they use cell line Huh7 ET(luc-ubi-neo/ET) containing a HCV RNA replicon with a luciferase (LUC)reporter. This particular construct has not been described in thescientific literature although it is similar to the cell line 5-2(Krieger et al. (2001) J. Virol. 75:4614-462.) and contains additionalmodifications that make the cell line more robust and provides forstable LUC expression for antiviral screening. This composition of thereplicon is shown as follows

5′-Luc-Ubiq-Neo - - - NS3-NS4A-NS4B-NS5A-NS5B-3′

The HCV RNA replicon ET contains the 5′ NTR (IRES) of HCV (5′) whichdrives the production of a firefly luciferase (Luc), ubiquitin (Ubiq),and neomycin phosphotransferase (Neo) fusion protein. Ubiquitin cleavagereleases the LUC and Neo genes. The EMCV IRES element (E-I) controls thetranslation of the HCV structural proteins NS3-NS5 and is locatedbetween Neo and NS3. The NS3 protein cleaves the HCV polyprotein torelease the mature NS3, NS4A, NS4B, NS5A and NS5B proteins that arerequired for HCV replication. At the 3′ end of the replicon is theauthentic 3′NTR of HCV. The LUC reporter is used as an indirect measureof HCV replication. The activity of the LUC reporter is directlyproportional to HCV RNA levels and positive control antiviral compoundsbehave comparably using either LUC or RNA endpoints.

RNA Replicon Assay

The effect of drug added in triplicate at concentrations of from e.g., 0to 100 uM using half log dilutions on HCV RNA-derived LUC activity andcytotoxicity. Human interferon alpha-2b is included in each run as apositive control compound. Subconfluent cultures of the ET line areplated out into 96-well plates that are dedicated for the analysis ofcell numbers (cytotoxicity) or antiviral activity and the next day drugsare added to the appropriate wells. Cells are processed 72 hr later whenthe cells are still subconfluent. Results from these assays are reportedin Table 1 below. Compound cytotoxicity is assessed as the percentviable cells relative to the untreated cell controls. This data is alsoreported. As is seen below Compound X has strong anti-HCV activity inthe 300-500 nanomolar range with a selectivity index (therapeutic index)in the range of 110-160.

TABLE 1 Activity of LSD1 inhibitor in an anti-HCV assay High TestAntiviral Cytotoxicity Selectivity Compound Concentration Activity EC₅₀IC₅₀ Index SI Compound X 100 uM 0.49 uM 54.81 uM 112 rIFNα-2b 2 IU/mL0.02 IU/mL >2 IU/mL >100 Compound X 100 uM <0.32 uM 50.55 uM 158rIFNα-2b 2 IU/mL 0.02 IU/mL >2 IU/mL >100 uM = μM

1-27. (canceled)
 28. A method of treating or preventing a Flaviviridaeinfection or a disease or disorder associated with Flaviviridaecomprising identifying an individual in need of such treatment andadministering to said individual a LSD1 inhibitor.
 29. The method ofclaim 28 wherein said Flaviviridae is Hepatitis C virus, Yellow fevervirus, West Nile Virus, Dengue Virus, or Japanese encephalitis virus.30. (canceled)
 31. The method of claim 28 wherein said LSD1 inhibitor isa reversible or irreversible amine oxidase inhibitor.
 32. The method ofclaim 28 wherein said LSD1 inhibitor inhibits Flaviviridae RNAreplication.
 33. The method of claim 28 wherein said LSD1 inhibitor is asmall molecule inhibitor of LSD1.
 34. The method of claim 28 whereinsaid LSD1 inhibitor is a selective LSD1 inhibitor. 35-47. (canceled) 48.A method of treating or preventing a symptom of Hepatitis C virusinfection or a liver disease in an individual infected with Hepatitis Cvirus, the method comprising identifying an individual in need of suchtreatment and administering to said individual an LSD1 inhibitor. 49.(canceled)
 50. A method of treating or preventing HCV and HBVco-infection comprising identifying an individual in need of suchtreatment and administering to said individual an LSD1 inhibitor andoptionally a second anti-HCV agent or anti-HBV agent.
 51. The method ofclaim 28, wherein said LSD1 inhibitor is a 2-cyclylcyclopropan-1-aminecompound, a phenelzine compound, or a propargylamine compound.
 52. Themethod of claim 28, wherein said LSD1 inhibitor is2-arylcyclopropan-1-amine compound or a 2-heteroarylcyclopropan-1-aminecompound. 53-54. (canceled)
 55. The method of claim 28, wherein saidLSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound of formula (I)or an enantiomer, a diastereomer, or a racemic mixture thereof, or apharmaceutically acceptable salt or solvate thereof:

wherein: A is cyclyl optionally having 1, 2, 3, or 4 substituents A′;each A′ is independently selected from -L¹-cyclyl, alkyl, alkenyl,alkynyl, alkoxy, amino, amido, —CH₂—CO—NH₂, alkylamino, hydroxyl, nitro,halo, haloalkyl, haloalkoxy, cyano, sulfonyl, sulfinyl, sulfonamide,acyl, carboxyl, carbamate and urea, wherein the cyclyl moiety comprisedin said -L¹-cyclyl is optionally further substituted with one or moregroups independently selected from halo, haloalkyl, haloalkoxy, aryl,arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino,amido, alkylamino, hydroxyl, nitro, —CH₂—CO—NH₂, heteroaryl,heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cyano, sulfonyl,sulfinyl, sulfonamide, acyl, carboxyl, carbamate and urea; each L¹ isindependently selected from a covalent bond, —(CH₂)₁₋₆,—(CH₂)₀₋₃—O—(CH₂)₀₋₃—, —(CH₂)₀₋₃—NH—(CH₂)₀₋₃— and —(CH₂)₀₋₃—S—(CH₂)₀₋₃—;B is -L²-cyclyl, —H, -L²-CO—NH₂, -L²-CO—NR¹R² or -L²-CO—R³, wherein thecyclyl moiety in said -L²-cyclyl is optionally substituted with one ormore groups independently selected from halo, haloalkyl, haloalkoxy,haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl,alkoxy, amino, amido, alkylamino, hydroxyl, nitro, —CH₂—CO—NH₂,heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl,cycloalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy,heterocycloalkylalkyl, cyano, cyanato, isocyanato, thiocyanato,isothiocyanato, sulfonyl, sulfinyl, sulfonamide,trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio,cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio,carboxyl, carbamate and urea; R¹ and R² are each independently selectedfrom —H, alkyl, alkynyl, alkenyl, -L-carbocycle, -L-aryl, and-L-heterocyclyl, wherein said alkyl, said alkynyl or said alkenyl isoptionally substituted with one or more groups independently selectedfrom halo, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, alkoxy,amino, amido, alkylamino, hydroxyl, nitro, —CH₂—CO—NH₂, heteroaryl,heteroarylalkoxy, heteroaryloxy, cycloalkyl, cycloalkylalkoxy,cycloalkoxy, heterocycloalkyl, heterocycloalkylalkoxy,heterocycloalkoxy, cyano, cyanato, isocyanato, thiocyanato,isothiocyanato, sulfonyl, sulfinyl, sulfonamide,trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio,cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio,carboxyl, carbamate and urea, and further wherein the carbocycle moietyin said -L-carbocycle, the aryl moiety in said -L-aryl, or theheterocyclyl moiety in said -L-heterocyclyl is optionally substitutedwith one or more groups independently selected from halo, haloalkyl,haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl,alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl, nitro,—CH₂—CO—NH₂, heteroaryl, heteroarylalkoxy, heteroaryloxy,heteroarylalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkoxy,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy,heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato,thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide,trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio,cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio,carboxyl, carbamate and urea; R³ is selected from —H, alkoxy,-L-carbocyclic, -L-heterocyclic, and -L-aryl, wherein the carbocyclicmoiety in said -L-carbocyclic, the heterocyclic moiety in said-L-heterocyclic, or the aryl moiety in said -L-aryl is optionallysubstituted with one or more groups independently selected from halo,haloalkyl, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl,alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl,nitro, —CH₂—CO—NH₂, heteroaryl, heteroarylalkoxy, heteroaryloxy,heteroarylalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkoxy,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy,heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato,thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide,trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio,cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio,carboxyl, carbamate and urea; each L is independently selected from—(CH₂)_(n)—(CH₂)_(n)—, —(CH₂)_(n)C(═O)(CH₂)_(n)—,—(CH₂)_(n)C(═O)NH(CH₂)_(n)—, —(CH₂)NHC(═O)O(CH₂)_(n)—,—(CH₂)_(n)NHC(═O)NH(CH₂)_(n)—, —(CH₂)_(n)NHC(═S)S(CH₂)_(n)—,—(CH₂)_(n)OC(═O)S(CH₂)_(n)—, —(CH₂)_(n)NH(CH₂)_(n)—,—(CH₂)_(n)—O—(CH₂)_(n)—, —(CH₂)_(n)S(CH₂)_(n)—, and—(CH₂)_(n)NHC(═S)NH(CH₂)_(n)—, wherein each n is independently selectedfrom 0, 1, 2, 3, 4, 5, 6, 7, and 8; and L² is C₁₋₁₂ alkylene which isoptionally interrupted by one or more groups independently selected from—O—, —S—, —NH—, —N(alkyl)-, —CO—, —CO—NH— and —CO—N(alkyl)-, or L² is acovalent bond.
 56. The method of claim 55, wherein A is aryl orheteroaryl and wherein A is unsubstituted or has 1 or 2 substituents A′.57. (canceled)
 58. The method of claim 56, wherein A is phenyl,pyridinyl, pyrimidinyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl,furanyl, or thiazolyl and wherein A is unsubstituted or has 1 or 2substituents A′. 59-66. (canceled)
 67. The method of claim 55, wherein Bis -L²-cyclyl, and further wherein the cyclyl moiety in said -L²-cyclylis optionally substituted with one or more groups independently selectedfrom halo, haloalkyl, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy,arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino,hydroxyl, nitro, —CH₂—CO—NH₂, heteroaryl, heteroarylalkoxy,heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkylalkoxy,cycloalkoxy, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy,heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato,thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide,trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio,cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio,carboxyl, carbamate, and urea. 68-69. (canceled)
 70. The method of claim67, wherein the cyclyl moiety in said -L²-cyclyl is aryl or cycloalkyl.71. The method of claim, wherein the cyclyl moiety in said -L²-cyclyl isheteroaryl or heterocycloalkyl. 72-74. (canceled)
 75. The method ofclaim 55, wherein L² is —(CH₂)₁₋₄—, —CH₂—CO—, or a covalent bond. 76-82.(canceled)
 83. The method of claim 55, wherein B is —H.
 84. The methodof claim 55, wherein B is -L²-CO—NH₂, —(CH₂)₁₋₄—CO—NH₂, -L²-CO—NR¹R²,—(CH₂)₁₋₄—CO—NR¹R², -L²-CO—R³, or —(CH)₁₋₄—CO—R³. 85-92. (canceled) 93.The method of claim 55, wherein the substituents on the cyclopropanering are in trans configuration. 94-109. (canceled)